CN105085436B - Sulfonic acid amide derivatives and its application on drug - Google Patents

Sulfonic acid amide derivatives and its application on drug Download PDF

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Publication number
CN105085436B
CN105085436B CN201510188690.2A CN201510188690A CN105085436B CN 105085436 B CN105085436 B CN 105085436B CN 201510188690 A CN201510188690 A CN 201510188690A CN 105085436 B CN105085436 B CN 105085436B
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base
prepared
piperazine
title compound
group
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CN105085436A (en
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张英俊
金传飞
钟文和
谢洪朋
张
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Guangdong HEC Pharmaceutical
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Ruyuan Yongxing Technical Service Co Ltd
Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

The present invention provides a kind of sulfonic acid amide derivatives or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, for treating Alzheimer's disease.The invention further relates to the pharmaceutical composition comprising the compounds of this invention and the compounds of this invention or its pharmaceutical composition in preparation treatment and 5-HT6Purposes in the drug of receptor related disease, especially Alzheimer's disease.

Description

Sulfonic acid amide derivatives and its application on drug
Technical field
The invention belongs to drug fields, and in particular to for treating the compound of Alzheimer's disease, comprising the chemical combination The medical composition and its use of object.Particularly, compound of the present invention is to can be used as 5-HT6The sulphur of receptor antagonist Amide derivatives.
Background technique
A variety of central nervous system diseases such as anxiety, depression etc. with neurotransmitter serotonin (5-HT) or thrombocytin Disorder it is related.As modulability neurotransmitter main in brain, the function of neurotransmitter serotonin (5-HT) be pass through by Referred to as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6And 5-HT7A large amount of receptor families mediate.Based on Gao Shui in brain Flat 5-HT6Receptor mrna, it has been suggested that 5-HT6Receptor may play in the pathology of central nervous system disorders and treatment Effect.Specifically, it has been determined that 5-HT6Selective ligands have potential treatment work to certain CNS (central nervous system) illness With, such as Parkinson's disease, Huntington's chorea, anxiety disorder, depression, manic-depressive psychosis, mental disease, epilepsy, obsessive-compulsive disorder, inclined head Bitterly, Alzheimer's disease (cognition and memory enhancing), sleep disturbance, eating disorder (such as anorexia and bulimia nerovsa), terrified hair Work, ADHD (attention deficit hyperactivity disorder), attention deficit disorder, drug abuse (such as ***e, ethyl alcohol, nicotine and Benzodiazepine class) caused by take off recessive brain syndrome, schizophrenia and related with spinal trauma or head injury Illness (such as hydrocephalus).It is expected that the 5-HT6Selective ligands can also be used to treat certain stomach intestinal disease such as functional bowel disorders. (see, for example, Roth, B.L., etc., J.Pharmacol.Exp.Ther., 1994,268,1403-14120；Sibley, D.R., Deng, Mol, Pharmacol., 1993,43,320-327；Sleight, A.J., etc., Neurotransmission, 1995,11, 1-5 and Sleight, A.J., etc. Serotonin ID Research Alert, 1997,2 (3), 115-8).
The study found that known 5-HT6Receptor selective antagonists can significantly improve the glutamic acid in cortex of frontal lobe With the level of aspartic acid, the level of hormone, dopamine or 5-HT on first kidney is gone without improving.It is this in memory and cognitive process In notice specific neurochemical selectivity raising strongly suggested that 5-HT6Effect of the ligand in cognition (Dawson,L.A.；Nguyen,H.Q.；Li,P.,British Journal of Pharmacology,2000,130(1), 23-26).With known selectivity 5-HT6Research that receptor antagonist carries out the memory of animal and study have it is some actively Effect (Rogers, D.C.；Hatcher, P.D.；Hagan, J.J., Society of Neuroscience, Abstracts, 2000,26,680).5-HT6The related potential treatment purposes of ligand is to treat the attention deficit disorder of children and adult.Because 5-HT6Receptor antagonist seems to improve the activity of nigrostriatal dopamine approach, and because in ADHD and caudate nucleus Exception related (Ernst, M；Zametkin, A.J.；Matochik, J.H.；Jons, P.A.；Cohen, R.M., Journal Of Neuroscience, 1998,18 (5), 5901-5907), so, 5-HT6Receptor antagonist can treat attention deficit Disease.Have also been determined that 5-HT6Receptor antagonist is the potentially useful compound for treating obesity.See, for example, Bentley etc., Br.J.Pharmac.1999, supplementary issue 126；Bentley etc., J.Psychopharmacol.1997, supplementary issue A64:255；Wooley Deng Neuropharmacology 2001,41:210-129 and WO02098878.
Summary of the invention
The present invention provides one kind to have 5-HT6The sulfamide compound of receptor antagonist activity has and preferably faces Bed application prospect.Compared with existing similar compound, the compound of the present invention is to 5-HT6Receptor has high affinity and right This receptor shows highly selective, while having better drug effect, medicine for property and/or toxicological characteristics, such as good biology Utilization rate and/or good metabolic stability.
The present invention relates to the sides of the sulfonic acid amide derivatives of new treatment Alzheimer's disease and treatment Alzheimer's disease Method.The compounds of this invention and pharmaceutical composition comprising the compound are to 5-HT6Receptor has preferable affinity interaction, especially There is preferable therapeutic effect to Alzheimer's disease.
On the one hand, the present invention relates to a kind of compounds, are formula (I) or (I-A) compound represented or formula (I) or (I- A the stereoisomer of compound shown in), geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolism Product, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2 or 3；
M is 0,1,2,3 or 4；
N is 1,2,3 or 4；
Each X independently is CH or N, and most two X are simultaneously N；
Each Y independently is CH or N；
Each R1And R3It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, C3-8Naphthenic base, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Alkylthio group, C1-6Alkenylthio group, R9R9aN- C1-6Alkyl ,-C (=O) R9b,-C (=O) OR9c,-C (=O) NR9R9a、R9R9aN-S (=O)2-、R9bS (=O)2-、R9bS (= O)-C1-6Alkyl, R9R9aN-C (=O)-C1-6Alkyl, C6-10Aryl, C6-10Fragrant amino, 5-12 former molecular heteroaryl, (C3-8Naphthenic base)-(C1-6Alkyl)-, (3-12 former molecular heterocycle)-(C1-6Alkyl)-, (C6-10Aryl)-(C1-6Alkane Base)-, (5-12 former molecular heteroaryl)-(C1-6Alkyl)-or 3-12 former molecular heterocycle；
Each R2It independently is H, D, F, Cl, Br, I ,-CN ,-OH ,-NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkanes Base, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy or C6-10Aryl or adjacent two R2It is connected with them Carbon atom is formed together substituted or unsubstituted 5-7 former molecular carbocyclic ring, 5-7 former molecular heterocycle, phenyl ring or 5-6 A molecular hetero-aromatic ring of original；
R4For H, D, C1-6Alkyl, halogenated C1-6Alkyl, C3-8Naphthenic base ,-C (=O) R9b,-C (=O) NR9R9a、C2-6Alkenyl Or C2-6Alkynyl；
R5、R6、R7And R8It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、C1-6Alkyl, C2-6Alkene Base, C2-6Alkynyl, 3-12 former molecular heterocycle, C3-8Naphthenic base ,-C (=O) R9bOr-C (=O) NR9R9a；
Or R5And R6Or R7And R8, and together with the carbon atom that they are connected, it is separately formed substituted or unsubstituted 3-8 A molecular carbocyclic ring of original or 3-8 former molecular heterocycle；
R10For 3-12 former molecular heterocycle, C3-8Naphthenic base, C6-10Aryl or 5-12 former molecular heteroaryl Base, wherein described 3-12 former molecular heterocycle, C3-8Naphthenic base, C6-10Aryl and 5-12 former molecular heteroaryl H, D, F, Cl, Br, I ,-CN, oxo (=O) ,-C (=O) R are independently selected from by 1,2,3 or 4 individually optionally9b,-C (=O) OR9c,-C (=O) NR9R9a、C1-6Alkyl, C3-8Naphthenic base, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, (C6-10 Aryl)-(C1-6Alkyl)-or (5-12 former molecular heteroaryl)-(C1-6Alkyl)-substituent group replaced；With
Each R9、R9a、R9bAnd R9cIt independently is H, D ,-OH, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, C6-10Aryl, 3-12 former molecular heterocycle, C3-8Naphthenic base, (C6-10Aryl)-(C1-6Alkyl)-, C6-10Aryloxy group, 3-12 atom group At heterocycle oxygroup, C3-8Cycloalkyl oxy, C6-10Fragrant amino, 3-12 former molecular heterocyclylamino group, C3-8Naphthenic base Amino or 5-12 former molecular heteroaryl or R9And R9aSubstitution is formed together with the nitrogen-atoms that they are connected simultaneously or is not taken The former molecular ring of 3-8 of generation.
In one embodiment, R in formula (I) or (I-A)10For 3-8 former molecular heterocycle, wherein the heterocycle Optionally H, D, F, Cl, Br, I ,-CN, oxo (=O) ,-C (=O) R are independently selected from by 1,2,3 or 49b,-C (=O) OR9c、- C (=O) NR9R9a、C1-4Alkyl, C3-6Naphthenic base, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkoxy, (C6-10Aryl)- (C1-4Alkyl)-or (5-12 former molecular heteroaryl)-(C1-4Alkyl)-substituent group replaced；With
Each R9、R9a、R9bAnd R9cIt independently is H, D ,-OH or C1-4Alkyl.
In one embodiment, compound of the present invention is formula (II) or (II-A) compound represented or formula (II) or the stereoisomer of compound shown in (II-A), geometric isomer, tautomer, nitrogen oxides, hydrate, solvent Compound, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
Q is CH, N or N → O；
M is-NR11Or-O-；
R11For H, D, C1-6Alkyl or halogenated C1-6Alkyl；With
Each R1、R2、R3、R4、R5、R6、R7、R8, Y, m, k and n have meaning of the present invention.
In another embodiment, each R in formula (I), (I-A), (II) or (II-A)1And R3Independently be H, D, F, Cl, Br、I、-CN、-OH、-NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Naphthenic base, halogenated C1-4Alkyl, C1-4Alkoxy, halogen For C1-4Alkoxy, 3-8 former molecular heterocycle, 5-9 former molecular heteroaryl or C6-10Aryl.
In another embodiment, each R in formula (I), (I-A), (II) or (II-A)2Independently be H, D, F, Cl, Br, I、-CN、-OH、-NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Naphthenic base, halogenated C1-4Alkyl, C1-4It is alkoxy, halogenated C1-4Alkoxy or C6-10Aryl or adjacent two R2Substituted or unsubstituted benzene is formed together with the carbon atom being connected with them Ring or 5-6 former molecular hetero-aromatic ring.
In another embodiment, R in formula (I), (I-A), (II) or (II-A)5、R6、R7And R8Be each independently H, D、F、Cl、Br、I、-CN、-NO2、-OH、-NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl or C3-6Naphthenic base；
Or R5And R6Or R7And R8, and together with the carbon atom that they are connected, it is separately formed substituted or unsubstituted 3-6 A molecular carbocyclic ring of original.
In yet another embodiment, each R in formula (I), (I-A), (II) or (II-A)1And R3Independently be H, D, F, Cl, Br、I、-CN、-OH、-NH2, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, methoxyl group, ethyoxyl, Positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, morpholinyl, piperazinyl, tetrahydro Furyl, nafoxidine base, tetrahydro-thienyl or 1,4- dioxane.
In yet another embodiment, each R in formula (I), (I-A), (II) or (II-A)2Independently be H, D, F, Cl, Br, I、-CN、-OH、-NH2, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, methoxyl group, ethyoxyl, just Propoxyl group, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl or fluorine-substituted C1-4Alkoxy, Or two adjacent R2Substituted or unsubstituted phenyl ring is formed together with the carbon atom being connected with them.
In yet another embodiment, R in formula (II) or (II-A)4And R11It is each independently H, D, methyl, ethyl, positive third Base, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl.
In yet another embodiment, R in formula (I), (I-A), (II) or (II-A)5、R6、R7And R8Be each independently H, D、F、Cl、Br、I、-OH、-NH2, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl or ring Butyl；
Or R5And R6Or R7And R8, and together with the carbon atom that they are connected, it is separately formed cyclopropane, cyclobutane, ring Pentane or hexamethylene.
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes the compound of the present invention.
In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable carrier, Excipient, diluent, adjuvant, medium or their any combination.
In another embodiment, pharmaceutical composition of the present invention further includes additional therapeutic agent, wherein institute Stating additional therapeutic agent is the drug for treating azheimer's disease, the drug or their combination for treating nervous disorders.
In yet another embodiment, additional therapeutic agent of the present invention is donepezil (donepezil), nalmefene (nalmefene), Risperidone (risperidone), vitamin e (Vitamin E), SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, idalopirdine, Tacrine (tacrine), Rivastigmine (rivastigmine), galanthamine (galantamine), Memantine (memantine), rice he Prick flat (Mirtazapine), Venlafaxine (venlafaxine), desipramine (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zopiclone), Nicergoline (nicergoline), pyrrole La Xitan (piracetam), selegiline (selegiline), pentoxifylline (pentoxifylline) or theirs is any Combination.
On the other hand, the purposes the present invention relates to the compounds of this invention or pharmaceutical composition in medicine preparation, the medicine Object is used to prevent, treat or mitigate and 5-HT6Receptor related disease.
In one embodiment, the present invention relates to 5-HT6Receptor related disease is CNS illness.
In another embodiment, the present invention relates to 5-HT6Receptor related CNS illness be ADHD, anxiety, with spirit Nervous relevant disease, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nervous disorders, memory disorders, note Meaning power defect obstacle, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's chorea.
In one embodiment, the present invention relates to 5-HT6Receptor related disease is disorder of gastrointestinal tract.
In one embodiment, the present invention relates to 5-HT6Receptor related disease is obesity.
Another aspect of the present invention is related to the preparation of formula (I), (I-A), (II) or (II-A) compound represented, separation and pure The method of change.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.All bibliography in this specification pass through whole reference In this.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used herein should be applied.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.
There is apparent conflict unless otherwise indicated or in context, the article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by Trying object is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans) isomers, atropisomer, etc..
Term " chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be with its mirror image The molecule of overlapping.
Term " enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
Term " racemate " or " racemic mixture " be optically active two enantiomters of hypodactylia etc. rub That mixture.
Term " diastereoisomer " refer to there are two or multiple chiral centers and its molecule not solid of mirror image each other Isomers.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereo-isomerism Body mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound The symbol turned, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy When anisotropic, such case may occur in which.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, and this is retouched It states and includes the case where the case where wherein event or situation occur and wherein it does not occur.For example, " optional key " refers to The key may exist or can be not present, and the description includes singly-bound, double or triple bonds.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
One or more degrees of unsaturation are contained in term " unsaturation " or " unsaturated " expression part.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or unsubstituted ".In general, art Language " substitution " or " substituted " the one or more hydrogen atoms indicated in given structure are replaced specific substituent group.Unless other Aspect shows that an optional substituent group can be replaced at various substitutable position of that group.When given structure In formula more than one position can by selected from specific group one or more substituent groups replaced, then substituent group can it is identical or Differently replace at various locations.Wherein the substituent group can be, but be not limited to, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, Iodine, cyano, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio group, alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, Sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, halogenated alkyl, halogenated alkoxy, hydroxyl replace alkyl, Alkyl-C (=O)-, the alkyl-C (=O)-, alkyl-that alkoxy, the hydroxyl of halogenated alkyl, hydroxyl substitution that hydroxyl replaces replace S (=O)-, alkyl-S (=O)2, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2, carboxyl alcoxyl Base, etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.For example, structural formula "-C (=O) NR9R9a" and structural formula " R9R9aN-S (=O)2" R between the two9And R9aSpecific option it is unaffected from each other.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Contain 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.In some specific structures, When alkyl group clearly shows that as linking group, then the alkyl group represents the alkylidene group of connection, for example, structural formula (C3-8Naphthenic base)-(C1-6Alkyl)-in C1-6Alkyl should be understood as C1-6Alkylidene.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3) CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " alkylidene " expression removes the two of two obtained saturations of hydrogen atom from the linear chain or branched chain hydrocarbon of saturation Valency alkyl group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylidene Group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In another embodiment In, alkylidene group contains 1-3 carbon atom；Also in one embodiment, alkylidene group contains 1-2 carbon atom.In this way Example include methylene (- CH2), ethylidene (- CH2CH2), isopropylidene (- CH (CH3)CH2), etc..The alkylidene Group is optionally replaced one or more substituent groups described in the invention.
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein the alkenyl group is optionally by one or more described in the invention Replaced substituent group comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".In one embodiment, alkene Base group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another embodiment In, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH=CH2), alkene Propyl (- CH2CH=CH2), etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group is optionally by one or more described in the invention Replaced substituent group.In one embodiment, alkynyl group includes 2-8 carbon atom；In another embodiment, alkynyl group Include 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example of alkynyl group includes, But it is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyl (- C ≡ C-CH3), etc..
Term " H " indicates single hydrogen atom.Such atomic group can be connect with other groups, for example with oxygen atom phase Even, hydroxyl group is formed.
Term " D " or "2H " indicates single D-atom.One such atomic group is connected with a methylene, is formed mono- Deuterated methyl (- CDH2)；Two D-atoms are connected with a methine, form double-deuterated methyl (- CD2H)；And three deuterium originals Son is connected with the carbon atom of a tetravalence, forms tris-methyl (- CD3)。
Term " hetero atom " indicates one or more oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), The form of sulphur (S) and phosphorus (P) any oxidation state；The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the hydrogen in heterocycle on nitrogen-atoms Substituted form, for example, N (as the N in 3,4- dihydro-2 h-pyrrole base), NH (as the NH in pyrrolidinyl) or NR are (as N- NR in substituted pyrrolidinyl).
Term " halogen " and " halogenated " refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " halogenated alkyl ", " halogenated alkenyl " or " halogenated alkoxy " indicate alkyl, alkenyl or alkoxy base by one Replaced a or multiple halogen atoms, wherein alkyl, alkenyl and alkoxy base have meaning of the present invention, such reality Example includes, but is not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2,2,2- trifluoro ethoxies, 2,2,3,3- tetrafluoros Propoxyl group, etc..The halogenated alkyl, halogenated alkenyl or halo alkoxy group are optionally retouched by one or more present invention Replaced the substituent group stated.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base is optionally by this one or more hair Replaced the substituent group of bright description.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxy (n- amoxy ,-OCH2CH2CH2CH2CH3), 2- amoxy (- OCH (CH3) CH2CH2CH3), 3- amoxy (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourth Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " fluorine-substituted C1-4Alkoxy " indicates C1-4The alkoxy of linear chain or branched chain is by one or more fluorine (F) atom Replaced, wherein alkoxy base has meaning of the present invention, and such example includes, but is not limited to, difluoromethoxy Base, trifluoromethoxy, 2- fluorine ethyoxyl, 2,2- difluoroethoxy, 2,2,2- trifluoro ethoxy, 2,3- difluoro propoxyl group, 2,3, 3- trifluoro propoxyl group, 2,3,3,3- tetrafluoro propoxyl group, 2,2,3- trifluoro propoxyl group, 2,2,3,3- tetrafluoro propoxyl group, 2,2,3,3, Five fluorine propoxyl group of 3-, etc..The fluorine-substituted C1-4Alkoxy base optionally described in the invention is taken by one or more Replaced Dai Ji.
Term " alkylthio group " refers to that the alkyl of linear chain or branched chain is connected by sulphur atom with molecule rest part, wherein alkyl Group has meaning of the present invention.In one embodiment, alkylthio group is the C of lower level1-4Alkylthio group, such example Include, but is not limited to methyl mercapto (CH3S-).The alkylthio radicals optionally described in the invention are taken by one or more Replaced Dai Ji.
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.? In one embodiment, alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms. In another embodiment, alkyl amino is C1-3Lower level alkylamino group.Suitable alkylamino group can be Alkyl monosubstituted amino or dialkyl amido, such example include, but is not limited to, N- methylamino, N- ethylamino, N, N- diformazan ammonia Base, N, N- lignocaine etc..The alkylamino radicals are optionally taken by one or more substituent groups described in the invention Generation.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular heterocycles of original.
Term " ring " includes carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring, etc., wherein the carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring Group has meaning as described in the present invention.
Term " carbocylic radical " or " carbocyclic ring " indicate containing 3-12 carbon atom, monovalent or multivalence monocycle, it is bicyclic or Three-ring system, middle ring can be fully saturated or comprising one or more degrees of unsaturation, but an armaticity ring all cannot Have.Carbon bicyclic group includes spiral shell carbon bicyclic group, bridge carbon bicyclic group and condensed carbon bicyclic group, and suitable carbocylic radical group includes, but simultaneously It is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.The example of carbocylic radical group further comprises, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- cyclohexyl -1- alkenyl, 1- hexamethylene Base -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, Cyclo-dodecyl, etc..The carbocylic radical group is optionally replaced one or more substituent groups described in the invention.? In one embodiment, " 3-6 former molecular carbocyclic ring " includes C3-6Naphthenic base, C3-6Cycloalkenyl and C3-6Cycloalkynyl radical.
Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.Bicyclic or three-ring system may include condensed ring, bridged ring and loop coil.In one embodiment, naphthenic base includes that 3-10 carbon is former Son；In another embodiment, naphthenic base includes 3-8 carbon atom；In yet another embodiment, naphthenic base includes 3-6 carbon Atom.The example of group of naphthene base includes, but are not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, etc..The cycloalkanes Base group is optionally replaced one or more substituent groups described in the invention.
Term " cycloalkyl-alkyl " indicate alkyl group replaced one or more groups of naphthene base, wherein naphthenic base and Alkyl group has meaning as described in the present invention, and such example includes, but is not limited to Cvclopropvlmethvl, cyclopropyl second Base, cyclopentyl ethyl, cyclohexyl-ethyl, cyclohexyl methyl, etc..The cycloalkylalkyl group is optionally one or more Replaced substituent group described in the invention.
Term " cycloalkyl oxy " or " carbocylic radical oxygroup " include that the naphthenic base optionally replaced or carbocylic radical are connected to oxygen original On son, and it is connected by oxygen atom with molecule rest part, wherein naphthenic base and carbocylic radical group have of the present invention contain Justice, such example include, but is not limited to cyclopropyl oxygroup, cyclopentyloxy, cyclohexyl oxygroup, the cyclopropyl that hydroxyl replaces Oxygroup, etc..The cycloalkyl oxy or carbocylic radical oxygroup group are optionally by one or more substitutions described in the invention Replaced base.
Term " cycloalkyl amino " indicates replaced the group of naphthene base that amino group is optionally replaced by one or two, Middle group of naphthene base has meaning as described in the present invention, and such example includes, but is not limited to cyclopropylamino, cyclopenta Amino, Cyclohexylamino, the cyclopropylamino that hydroxyl replaces, dicyclohexyl amino, Bicyclopropyl amino, etc..The cycloalkanes Base amino group is optionally replaced one or more substituent groups described in the invention.
Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to the monocycle comprising 3-12 annular atom, double Ring or three-ring system, independently selected from nitrogen, sulphur and oxygen atom, ring can be fully saturated one or more atoms in middle ring Or comprising one or more degrees of unsaturation, but an armaticity ring cannot all have.In one embodiment, heterocyclyl groups are 3- 8 yuan monocycle (2-6 carbon atom and be selected from N, the 1-3 hetero atom of O, S, in this S optionally by one or more oxygen atom institutes Substitution is obtained as SO, SO2Group) or 7-12 member it is bicyclic (4-9 carbon atom and selected from N, the 1-3 hetero atom of O, S, This S is optionally obtained replaced one or more oxygen atoms as SO, SO2Group).The heterocyclyl groups are optionally by one Replaced a or multiple substituent groups described in the invention.
Heterocycle can be carbon-based or heteroatom group.- the CH of its middle ring2Group is optionally substituted by-C (=O)-, ring Sulphur atom is optionally oxidized to S- oxide, and the nitrogen-atoms of ring is optionally oxidized to N- oxygen compound.The example of heterocycle Include, but are not limited to Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolin Base, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro Thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane Base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepine base, diaza base, sulphur azepine Base, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, etc..- CH in heterocycle2The example that group is substituted by-C (=O)- Include, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyl, phonetic Pyridine diketo, etc..The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base, thio-morpholinyl 1,1- Dioxide, etc..The heterocyclyl groups are optionally replaced one or more substituent groups described in the invention.
In one embodiment, heterocycle is 4-7 former molecular heterocycle, refers to satisfying comprising 4-7 annular atom And/or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.4-7 former molecular heterocycle The example of base includes, but are not limited to azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- Pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, thiophane Base, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyrrole It mutters base, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base is high Piperazinyl, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepine base, diaza base, sulphur azepine base, etc. Deng.- CH in heterocycle2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1 by-C (=the O)-example substituted, 3- thiazolidinyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyl, hybar X base, etc..Sulphur atom is oxidized in heterocycle Example includes, but are not limited to sulfolane base, thio-morpholinyl 1,1- dioxide, etc..Described 4-7 is former molecular Heterocyclyl groups are optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 4 molecular heterocycles of original, refers to the saturation comprising 4 annular atoms Or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.4 molecular heterocycles of original Example includes, but are not limited to azelidinyl, oxetanylmethoxy, thietanyl, etc..4 originals are molecular miscellaneous Cyclic groups are optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 5 molecular heterocycles of original, refers to the saturation comprising 5 annular atoms Or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.5 molecular heterocycles of original Example includes, but are not limited to pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, Imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur rings penta Base, etc..- CH in heterocycle2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxygen by-C (=the O)-example substituted Generation -1,3-thiazoles alkyl, etc..The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base, etc..Institute The 5 molecular heterocyclyl groups of original stated are optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 6 molecular heterocycles of original, refers to the saturation comprising 6 annular atoms Or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.6 molecular heterocycles of original Example includes, but are not limited to THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidines Base, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base, etc..- CH in heterocycle2Group 2- piperidone base, 3,5- dioxy piperazine piperidinyl, hybar X base are included, but are not limited to by-C (=O)-example substituted, etc. Deng.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to thio-morpholinyl 1,1- dioxide, etc..Described 6 molecular heterocyclyl groups of original are optionally replaced one or more substituent groups described in the invention.
Also in one embodiment, heterocycle is 7-12 former molecular heterocycle.7-12 former molecular heterocycle The example of base includes, but are not limited to 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, etc..The 7-12 atom group At heterocyclyl groups optionally replaced one or more substituent groups described in the invention.
Term " heterocyclylalkyl group " indicates the alkyl that heterocycle replaces, and wherein heterocycle and alkyl have as described herein Meaning, such example includes, but is not limited to pyrrolidin-2-yl methyl, morpholine -4- base ethyl, etc..The heterocycle Alkyl is optionally replaced one or more substituent groups described in the invention.
Term " heterocycle oxygroup " indicates that the heterocycle optionally replaced is connected on oxygen atom as defined herein, And it is connected by oxygen atom with the rest part of molecule, such example includes, but is not limited to piperidin-2-yl oxygroup, piperidines- 3- base oxygroup, piperazine -2- base oxygroup, piperidin-4-yl oxygroup, etc..The heterocycle oxygroup group is optionally by one or more Replaced a substituent group described in the invention.
Term " heterocyclylamino group " indicates amino group replaced one or two heterocyclyl groups, and wherein heterocycle has There is meaning as described in the present invention, such example includes, but is not limited to, piperidin-2-yl amino, piperidines -3- base amino, piperazine Pyridine -4- base amino, piperazine -2- base amino, etc..The heterocyclylamino group group is optionally retouched by one or more present invention Replaced the substituent group stated.
Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring are aromatic.Aryl group is in general, but unnecessarily pass through aryl The armaticity ring of group is connect with parent molecule.Term " aryl " can be used interchangeably with term " aromatic ring ".The reality of aryl group Example may include phenyl, naphthalene and anthracene.The aryl group is optionally by one or more substituent group institutes described in the invention Replace.
Term " aralkyl " or " aryl alkyl " refer to the alkyl group that aryl replaces.In one embodiment, aralkyl Group refers to that " aralkyl of lower level " group, i.e. aryl group are connected to C1-6On alkyl group.In another embodiment, Aromatic alkyl group refers to containing C1-4" benzene alkyl " of alkyl.Wherein specific example includes benzyl, diphenyl methyl, phenethyl, etc. Deng.Aryl on aralkyl can be further by halogen, alkyl, alkoxy, replaced halogenated alkyl and halogenated alkoxy.It is described Aromatic alkyl group is optionally replaced one or more substituent groups described in the invention.
Term " aryloxy group " indicates that the aryl optionally replaced is connected on oxygen atom as defined herein, and by Oxygen atom is connected with molecule rest part, and wherein aryl group includes with meaning as described in the present invention, such example, but It is not limited to phenoxy group, toloxyl, ethylbenzene oxygroup, etc..The aryloxy group is optionally by one or more present invention Replaced described substituent group.
Term " fragrant amino " indicates amino group replaced one or two aryl group, and such example includes, but It is not limited to N- phenylamino.In one embodiment, the aromatic ring in fragrant amino can be further substituted.The fragrant amino group Optionally replaced one or more substituent groups described in the invention.
Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring are aromatic, and at least one ring includes one or more hetero atoms.It is miscellaneous Aryl group by the armaticity ring of heteroaryl groups with parent molecule in general, but unnecessarily connect.Term " heteroaryl " can With with term " hetero-aromatic ring ", " heteroaromatic " or " heteroaromatics " is used interchangeably.The heteroaryl groups are optionally by one Or replaced multiple substituent groups described in the invention.In one embodiment, 5-10 former molecular heteroaryl includes 1, 2,3 or 4 are independently selected from the hetero atom of O, S and N.
The example of heteroaryl groups includes, but is not limited to, 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazole Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazole Base (such as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3- Oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3- triazolyl, 1,2,3- thio biphosphole base, 1,3,4- sulphur For di azoly, 1,2,5- thio biphosphole base, pyrazinyl, cyanuro 1,3,5；Also include below bicyclic, but be not limited to these It is bicyclic: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinoline Quinoline base, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1, 2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine Base, etc..
Term " heteroaryl amino " indicates replaced the heteroaryl groups that amino group is optionally replaced by one or two, Middle heteroaryl has meaning as described in the present invention, and such example includes, but is not limited to, N- thienyl amino, pyridine -4- Base amino, fluorine pyridinylamino, bipyridyl amino, etc..The heteroaryl amino group is optionally one or more Replaced substituent group described in the invention.
Term " heteroaryloxy " indicates that the heteroaryl optionally replaced is connected on oxygen atom as defined herein, and And be connected by oxygen atom with molecule rest part, wherein heteroaryl groups have meaning as described in the present invention, such example Include, but is not limited to pyridine oxygroup, 2-pyrimidinyl oxy, etc..The heteroaryl oxygroup group is optionally by one or more sheets It invents replaced described substituent group.
Term " heteroaryl alkyl " indicate alkyl group replaced one or more heteroaryls, wherein heteroaryl and alkyl Group has meaning of the present invention, and such example includes, but is not limited to imidazoles -2- ylmethyl, furans -2- base second Base, indol-3-yl methyl, etc..The heteroarylalkyl group is optionally by one or more substitutions described in the invention Replaced base.
As described in the invention, substituent R is keyed to the ring system formed on the ring at center (such as formula f institute by one Show) it represents substituent R and only limits any on A ring may replace or any reasonable position is replaced.For example, formula f is represented on A ring Any possible substituted position can be substituted base R substitution, such as formula f1-f4It is shown:
Occur in the present invention structure "" indicateOr
Term " prodrug " used in the present invention, represent a compound be converted into vivo formula (I), (I-A), (I-B), (II), (II-A) or (II-B) compound represented.Such conversion is hydrolyzed by pro-drug in blood or in blood or group Knit the middle influence through enzymatic conversion for precursor structure.Pro-drug compounds of the present invention can be ester, the ester in existing invention It can be used as the phenyl ester class that has of pro-drug, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamate Class and amino acid esters.Such as a compound in the present invention includes hydroxyl, it can is acylated to obtain pro-drug shape The compound of formula.Other prodrug forms include phosphate, if these phosphate compounds are through the hydroxyl on parent What phosphorylation obtained.Following documents: Higuchi et al., Pro-drugs can be referred to by completely discussing about pro-drug as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,ed., Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications, Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every document pass through reference packet Contained in this.
Term " metabolite " used in the present invention refers to that specific compound or its salt passes through metabolism in vivo Obtained product.The metabolite of one compound can be identified by technology well-known in the art, active It can experimentally be characterized by adopting as described in the present invention.Such product can be through administrationization Object is closed through peroxidating, is restored, hydrolysis, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtains.Phase Ying Di, the present invention include the metabolite of compound, including when the compound of the present invention and mammal are come into full contact with one section Between generated metabolite.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., Documented by J.Pharmaceutical Sciences, 66:1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed It including, but is not limited to, inorganic acid salt formed by reacting with amino groups to form has a hydrochloride, hydrobromate, phosphate, sulfate, Perchlorate and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other are pharmaceutically acceptable Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonic acid Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid Salt, hydriodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, Malonate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake Sulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, Undecylate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4 Salt.The compound that the present invention is also intended to contemplate the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or Dispersion product can be obtained by quaternization.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy Upper acceptable salt further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenation Object, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used to block or protect the functionality of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy Ylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro second Base, etc..Description general for blocking group can refer to document: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.
Term " preventing " or " prevention " refer to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical condition of disease Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show The symptom of disease).
Term " ADHD " is the abbreviation of Attention-deficit hyperactivity disorder, means attention The mostly dynamic obstacle of defect, be it is a kind of childhood very common psychataxia.According to " the general disease in the world point of the World Health Organization Class handbook " the tenth edition (ICD-10, WHO, 1992) this disease be referred to as " hyperactivity disorder " (Hyperkinetic Disorder), point Class number is F90, general to be commonly called as again as " hyperactive children ".
Term " schizophrenia " refers to schizophrenia, schizophrenia-like disorder, schizoaffective disorder and spirit Characteristic of disease phrenoblabia, wherein term " mental disease " refers to vain hope, apparent illusion, amorphous language or unorganized behavior or deadlock Straightization behavior.Referring to Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington, D.C..
Pharmaceutical acid-addition salts can be acted on inorganic acid or organic acid by the compounds of this invention and be formed, such as acetate, Aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, Camsilate, chloride/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, Portugal Sugar lime, glucuronate, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, the moon Osmanthus base sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, Naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen Salt/dihydric phosphate, poly- galactolipin hydrochlorate, propionate, stearate, succinate, sulfosalicylate, tartrate, first Benzene sulfonate and trifluoroacetate.
The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be acted on inorganic base or organic base by the compounds of this invention and be formed.
Can obtain the inorganic base of salt by its derivative includes, for example, ammonium salt and periodic table I race to XII race metal.? In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
Can obtain the organic base of salt by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.
In addition, compound disclosed by the invention, the salt including them, in the form of their hydrate or can also include it The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as3H,14C and18Those of F compound, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichment to PET or It is especially desirable for SPECT research.Formula (I), (I-A), (I-B), (II), (II-A) or (II-B) institute of isotope enrichment Show that compound can be retouched by embodiment in routine techniques or the present invention familiar to those skilled in the art and preparation process It states and substitutes original used unmarked reagent using suitable isotope labeling reagent to prepare.
In addition, higher isotope especially deuterium (that is,2H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is seen as chemical combination shown in formula (I), (I-A), (I-B), (II), (II-A) or (II-B) The substituent group of object.The concentration of such higher isotope especially deuterium can be defined with isotope enrichment factor.The present invention is made Term " isotope enrichment factor " refers to the ratio between the isotope abundance and natural abundance of specified isotope.If The substituent group of the compounds of this invention is designated as deuterium, which has at least 3500 (respectively to refer to for each specified D-atom Determine at D-atom 52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporations), until Few 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporations), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporations), at least 6600 (99% deuterium incorporations) or at least The isotope enrichment factor of 6633.3 (99.5% deuterium incorporations).The pharmaceutical solvate of the present invention includes wherein recrystallisation solvent It can be such as D of isotope substitution2O, acetone-d6、DMSO-d6Those of solvate.
The description of the compounds of this invention
Sulfonic acid amide derivatives, its pharmaceutically acceptable salt, its pharmaceutical preparation and its pharmaceutical composition of the present invention Object has 5-HT6Receptor antagonism especially has potential purposes to the treatment of Alzheimer's disease.
On the one hand, the present invention relates to a kind of compound, be formula (I), (I-A) or (I-B) compound represented or its be Stereoisomer, geometric isomer, tautomer, the nitrogen oxides, hydration of compound shown in formula (I), (I-A) or (I-B) Object, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
Each k independently is 0,1,2 or 3；
Each m independently is 0,1,2,3 or 4；
Each n independently is 1,2,3 or 4；
Each X independently is CH or N in formula (I) or formula (I-A), and most two X are simultaneously N；
X, X in formula (I-B)1、X2And X3It is each independently CH or N, and X, X1、X2And X3In most two simultaneously be N；
Each Y and Y1It independently is CH or N；
Each R1And R3It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, C3-8Naphthenic base, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Alkylthio group, C1-6Alkenylthio group, R9R9aN- C1-6Alkyl ,-C (=O) R9b,-C (=O) OR9c,-C (=O) NR9R9a、R9R9aN-S (=O)2-、R9bS (=O)2-、R9bS (= O)-C1-6Alkyl, R9R9aN-C (=O)-C1-6Alkyl, C6-10Aryl, C6-10Fragrant amino, 5-12 former molecular heteroaryl, (C3-8Naphthenic base)-(C1-6Alkyl)-, (3-12 former molecular heterocycle)-(C1-6Alkyl)-, (C6-10Aryl)-(C1-6Alkane Base)-, (5-12 former molecular heteroaryl)-(C1-6Alkyl)-or 3-12 former molecular heterocycle；
Each R2It independently is H, D, F, Cl, Br, I ,-CN ,-OH ,-NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkanes Base, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy or C6-10Aryl or adjacent two R2It is connected with them Carbon atom is formed together substituted or unsubstituted 5-7 former molecular carbocyclic ring, 5-7 former molecular heterocycle, phenyl ring or 5-6 A molecular hetero-aromatic ring of original；
Each R4It independently is H, D, C1-6Alkyl, halogenated C1-6Alkyl, C3-8Naphthenic base ,-C (=O) R9b,-C (=O) NR9R9a、 C2-6Alkenyl or C2-6Alkynyl；
Each R5、R6、R7And R8It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, 3-12 former molecular heterocycle, C3-8Naphthenic base ,-C (=O) R9bOr-C (=O) NR9R9a；
Or R5And R6Or R7And R8, and together with the carbon atom that they are connected, it is separately formed substituted or unsubstituted 3-8 A molecular carbocyclic ring of original or 3-8 former molecular heterocycle；
Each R10It independently is 3-12 former molecular heterocycle, C3-8Naphthenic base, C6-10Aryl or 5-12 atom composition Heteroaryl, wherein 3-12 former molecular heterocycle, the C3-8Naphthenic base, C6-10Aryl and 5-12 original are molecular Heteroaryl is independently selected from H, D, F, Cl, Br, I ,-CN, oxo (=O) ,-C (=O) R by 1,2,3 or 4 individually optionally9b、-C (=O) OR9c,-C (=O) NR9R9a、C1-6Alkyl, C3-8Naphthenic base, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, (C6-10Aryl)-(C1-6Alkyl)-or (5-12 former molecular heteroaryl)-(C1-6Alkyl)-substituent group replaced；With
Each R9、R9a、R9bAnd R9cIt independently is H, D ,-OH, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, C6-10Aryl, 3-12 former molecular heterocycle, C3-8Naphthenic base, (C6-10Aryl)-(C1-6Alkyl)-, C6-10Aryloxy group, 3-12 atom group At heterocycle oxygroup, C3-8Cycloalkyl oxy, C6-10Fragrant amino, 3-12 former molecular heterocyclylamino group, C3-8Naphthenic base Amino or 5-12 former molecular heteroaryl or R9And R9aSubstitution is formed together with the nitrogen-atoms that they are connected simultaneously or is not taken The former molecular ring of 3-8 of generation.
In one embodiment, each R in formula (I), (I-A) or (I-B)10It independently is 3-8 former molecular heterocycle, Wherein the heterocycle is optionally independently selected from H, D, F, Cl, Br, I ,-CN, oxo (=O) ,-C (=O) by 1,2,3 or 4 R9b,-C (=O) OR9c,-C (=O) NR9R9a、C1-4Alkyl, C3-6Naphthenic base, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkane Oxygroup, (C6-10Aryl)-(C1-4Alkyl)-or (5-12 former molecular heteroaryl)-(C1-4Alkyl)-substituent group taken Generation；With
Each R9、R9a、R9bAnd R9cIt independently is H, D ,-OH or C1-4Alkyl.
In one embodiment, compound of the present invention is chemical combination shown in formula (II), (II-A) or (II-B) Object or its for compound shown in formula (II), (II-A) or (II-B) stereoisomer, geometric isomer, tautomer, nitrogen Oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
Q is CH, N or N → O；
M is-NR11Or-O-；
R11For H, D, C1-6Alkyl or halogenated C1-6Alkyl；With
Each R1、R2、R3、R4、R5、R6、R7、R8、Y、Y1, m, k and n have meaning of the present invention.
In another embodiment, each R in formula (I), (I-A), (I-B), (II), (II-A) or (II-B)1And R3Independently For H, D, F, Cl, Br, I ,-CN ,-OH ,-NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Naphthenic base, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkoxy, 3-8 former molecular heterocycle, 5-9 former molecular heteroaryl or C6-10Virtue Base.
In another embodiment, each R in formula (I), (I-A), (I-B), (II), (II-A) or (II-B)2It independently is H、D、F、Cl、Br、I、-CN、-OH、-NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Naphthenic base, halogenated C1-4Alkyl, C1-4 Alkoxy, halogenated C1-4Alkoxy or C6-10Aryl or adjacent two R2Substitution is formed together with the carbon atom being connected with them Or the former molecular hetero-aromatic ring of unsubstituted phenyl ring or 5-6.
In another embodiment, each R in formula (I), (I-A), (I-B), (II), (II-A) or (II-B)5、R6、R7And R8 It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-OH、-NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl or C3-6Naphthenic base；
Or R5And R6Or R7And R8, and together with the carbon atom that they are connected, it is separately formed substituted or unsubstituted 3-6 A molecular carbocyclic ring of original.
In yet another embodiment, each R in formula (I), (I-A), (I-B), (II), (II-A) or (II-B)1And R3Independently For H, D, F, Cl, Br, I ,-CN ,-OH ,-NH2, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, first Oxygroup, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, morpholine Base, piperazinyl, tetrahydrofuran base, nafoxidine base, tetrahydro-thienyl or 1,4- dioxane.
In yet another embodiment, each R in formula (I), (I-A), (I-B), (II), (II-A) or (II-B)2It independently is H、D、F、Cl、Br、I、-CN、-OH、-NH2, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, methoxy Base, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl or fluorine replace C1-4Alkoxy or adjacent two R2Substituted or unsubstituted phenyl ring is formed together with the carbon atom being connected with them.
In yet another embodiment, each R in formula (II), (II-A) or (II-B)4And R11It independently is H, D, methyl, second Base, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl.
In yet another embodiment, each R in formula (I), (I-A), (I-B), (II), (II-A) or (II-B)5、R6、R7And R8 It independently is H, D, F, Cl, Br, I ,-OH ,-NH2, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, Cyclopropyl or cyclobutyl；
Or R5And R6Or R7And R8, and together with the carbon atom that they are connected, it is separately formed cyclopropane, cyclobutane, ring Pentane or hexamethylene.
In one embodiment, the compounds of this invention includes the structure of one of:
Or it is vertical It is body isomers, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable Salt or prodrug.
The present invention also includes the application of the compound of the present invention and its pharmaceutically acceptable salt, for producing medical product Treat Alzheimer's disease and those illnesss described in the invention.The compound of the present invention is equally used for producing a kind of doctor Drug is for the alleviation, prevention, management or treatment of 5-HT6The illness that receptor is mediated, especially Alzheimer's disease.Packet of the present invention Drug containing compositions, the pharmaceutical composition include change representated by formula (I), (I-A), (I-B), (II), (II-A) or (II-B) Effective treatment dosage needed for closing the combination of object and at least one pharmaceutically acceptable carrier, adjuvant or diluent.
Unless otherwise indicated, all suitable isotope variations of the compound of the present invention, stereoisomer, mutually variation Structure body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to model of the invention It encloses.
Unless otherwise indicated, structural formula described in the invention includes that (such as mapping is different for all isomeric forms Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism)): such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right Reflect isomers, the mixture of diastereoisomer or geometric isomer (or conformer) belongs to the scope of the present invention.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
Disclosed compound of present invention can contain asymmetric or chiral centre, therefore can be with different stereoisomer forms In the presence of.The present invention is directed to all solids of compound shown in formula (I), (I-A), (I-B), (II), (II-A) or (II-B) are different Structure body form, including but not limited to diastereoisomer, enantiomter, atropisomer and geometry (or conformation) isomers, And their mixture such as racemic mixture, become component part of the invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
On the other hand, the present invention relates to chemical combination shown in preparation formula (I), (I-A), (I-B), (II), (II-A) or (II-B) The intermediate of object.
On the other hand, the present invention relates to compounds shown in formula (I), (I-A), (I-B), (II), (II-A) or (II-B) The method of preparation, separation and purifying.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must Must be suitble to chemistry or toxicologically, it is related with the other components of composition preparation and mammal for treatment.
The salt of the compound of the present invention further include be used to prepare or purify formula (I), (I-A), (I-B), (II), (II-A) or (II-B) purifying of compound shown in the intermediate or formula (I), (I-A), (I-B), (II), (II-A) or (II-B) of compound shown in Enantiomter salt, but be not necessarily pharmaceutically acceptable salt.
If the compound of the present invention be it is alkaline, conceivable salt can be by provided in the literature any suitable Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid；Pyrans Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino acid, such as asparatate and paddy Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethanesulfonic acid, etc..
If the compound of the present invention be it is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitable salt includes, but is not limited to, organic salt obtained from amino acids, such as glycine and arginine, ammonia, and such as primaquine, secondary Ammonia and tertiary ammonia and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium Inorganic salts.
The compounds of this invention and pharmaceutical composition, preparation and administration
When available for treatment, shown in the formula (I), (I-A), (I-B), (II), (II-A) or (II-B) of therapeutically effective amount Compound and its pharmaceutically acceptable salt can be used as unprocessed chemicals and give, and be alternatively arranged as the activity of pharmaceutical composition Ingredient provides.Therefore, the present invention also provides a kind of pharmaceutical composition, including formula (I), (I-A), (I-B), (II), (II-A) or (II-B) compound represented or its individual stereoisomer, the racemic or non-racemic mixture or its pharmacy of isomers Upper acceptable salt or solvate.In an embodiment of the invention, described pharmaceutical composition further includes at least A kind of pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, others treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.
It further comprise carrying out other to patient to resist comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered The administration of Alzheimer disease drug (combination therapy), wherein the drug of other anti-Alzheimer diseases is donepezil, Na Mei Sweet smell, Risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX- 8066, SB-742457, naluzaton, idalopirdine, Tacrine, Rivastigmine, galanthamine, Memantine, meter Ta Zha Flat, Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, hexanone can Theobromine or their combination.
Term as used herein " therapeutically effective amount " refers to each active group for being enough to show significant patient benefit The total amount divided.When using separate active ingredients for separate administration, which only refers to the ingredient.When combining applications, the term Then refer to the combined amount for regardless of combination, sequential or simultaneous administration all causing the active constituent of therapeutic effect.Formula (I), (I-A), (I-B), compound shown in (II), (II-A) or (II-B) and its pharmaceutically acceptable salt are as described above.From with preparation other Ingredient is compatible and in the sense that its recipient is harmless, and carrier, diluent or excipient must be acceptable.According to The another aspect of present disclosure, also provides method for preparing pharmaceutical preparations, and this method includes by formula (I), (I-A), (I- B), compound shown in (II), (II-A) or (II-B) or its pharmaceutically acceptable salt with it is one or more pharmaceutically acceptable Carrier, diluent or excipient mix.Term " pharmaceutically acceptable " used in the present invention refer to such compound, Raw material, composition and/or dosage form, they within the scope of reasonable medical judgment, be suitable for contacted with patient tissue and without excessive Toxicity, irritation, allergy or other problems relative to a reasonable benefit/risk ratio and complication, and effective for Given application.
In general, the compound of the present invention is by any conventional application method of the substance for playing similar effectiveness to treat Effective quantity is administered.Suitable dosage range is typically daily 1-500mg, preferably daily 1-100mg, most preferably daily 1- 30mg, this depends on many factors, such as age and the relative health, institute of the seriousness of treated disease, subject With the effect of compound, the approach of application and form, the preference of the targeted indication and related medical practitioner of application and Experience.The those of ordinary skill for treating the disease areas relies on personal knowledge and disclosure of this application without excessive experiment It can determine that the therapeutically effective amount of the compounds of this invention for giving disease.
In general, the compound of the present invention is applied with pharmaceutical preparation form, the pharmaceutical preparation includes that those are suitable for taking orally (including oral cavity and sublingual), rectum, nose, part, lung, vagina or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and vein It is interior) application pharmaceutical preparation or the pharmaceutical preparation suitable for sucking or being blown into administration form.Preferred method of application is usually to take orally, Using suitable daily dose plan, it can be adjusted according to illness degree.
One or more compounds of the invention can be placed in together with one or more conventional adjuvants, carrier or diluent In pharmaceutical composition and unit dosage form.Pharmaceutical composition and unit dosage form may include the conventional ingredient of conventional ratio, With or without other reactive compound or ingredient, unit dosage form can contain and applied planned daily dose range phase Any suitable a effective amount of active constituent claimed.The application form of pharmaceutical composition can be solid such as tablet or filling glue Wafer, semisolid, powder, sustained release preparation or liquid such as solution, suspension, emulsion, elixir or the filling glue being administered orally Wafer；Or for rectum or the suppository form of vaginal application；Or the sterile injectable solutions form for parenterally using. Therefore, in every containing about 1mg active constituent or more broadly, the preparation containing about 0.01 to about 100mg active constituent is suitable Representative unit dosage form.
The compound of the present invention can be configured to the dosage form of various oral administrations.Pharmaceutical composition and dosage form can Using comprising one or more compound or pharmaceutically acceptable salt thereofs of the invention as active constituent.Pharmaceutical carrier can be solid Or liquid.The preparation of solid form includes: powder, tablet, pill, capsule, cachet, suppository and dispersible granule. Solid carrier can be one or more substances, be also used as diluent, corrigent, solubilizer, lubricant, suspending agent, Adhesive, preservative, tablet disintegrant or coating material.In powder, carrier is usually finely ground solid, with finely ground work Property ingredient formed mixture.In tablets, active constituent is usually with the carrier with required adhesive force with suitable ratio phase It mixes and is pressed into required shapes and sizes.Powder and tablet preferably comprise from about the reactive compound of 1% to about 70%.It is suitable for Carrier include but is not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, the yellow alpine yarrow in west Glue, methylcellulose, sodium carboxymethylcellulose, low melt wax, cocoa butter etc..Terms " formulation " is intended to include containing coating material As carrier to provide the preparation of the reactive compound of capsule, the active constituent quilt of with or without carrier in the capsule The carrier in combination is surrounded.It similarly, further include cachet and pastille.Tablet, powder, capsule, pill, cachet It is adapted for the solid form being administered orally with pastille.
Other forms for being suitable for being administered orally include preparation (including emulsion, syrup, elixir, the aqueous solution of liquid form Agent, aqueous suspension) or it is intended to preparation using the preceding solid form for being changed into liquid form preparation at once.Emulsion can be molten Emulsifier such as lecithin, Sorbitan Monooleate or Arab are prepared or can contained in liquid such as aqueous solution of propylene glycol Glue.Active constituent can be by being dissolved in water and suitable colorant, corrigent, stabilizer and thickening being added by aqueous solution agent It is prepared by agent.Aqueous suspension can be by with for example natural or synthetic glue of stickum, resin, methylcellulose, carboxymethyl Finely ground active constituent is dispersed in water to prepare by sodium cellulosate and other well known suspending agent.The preparation of liquid form includes Solution, suspension and emulsion, it can also contain colorant, corrigent, stabilizer, buffer, people other than active constituent Sweetener make and natural, dispersing agent, thickener, solubilizer etc..
The compound of the present invention can be prepared for parenteral administration (for example, passing through injection such as bolus injection or continuous defeated Note application) and can be present in a unit ampoule, in advance filling syringe, in low capacity infusion or be present in It is added in the multi-dose container of preservative.The adoptable form of composition has suspension for example in oily or aqueous excipients Agent, solution or emulsion, such as solution in polyethylene glycol solution.Oiliness or non-aqueous carrier, diluent, solvent or The example of excipient includes propylene glycol, polyethylene glycol, vegetable oil (such as olive oil) and organic esters for injection (such as oleic acid second Ester), and formulating substances such as preservative, wetting agent, emulsifier or suspending agent, stabilizer and/or dispersing agent can be contained.Alternatively, Active constituent can be powder type, preparation method be sterile solid is carried out it is aseptic subpackaged or by by solution be lyophilized so as to Using preceding with suitable excipient is for example sterile, pyrogen-free water is constructed.
The compound of the present invention can be prepared in the form of ointment, cream or lotion or in a form of transdermal patch office Portion is applied to epidermis.Ointment and cream can be for example with being added to the aqueous or oily of suitable thickener and/or gelling agent Property matrix is prepared.Lotion can be prepared with water or oily matrix and usually also contain one or more emulsifying agents, steady Determine agent, dispersing agent, suspending agent, thickener or colorant.Suitable for mouth the preparation of local application include: in the base through flavoring It include the pastille of activating agent in matter, the matrix through flavoring is usually sucrose and Arabic gum or tragacanth；In inertia base Contain the pastille of active constituent, the inert base such as gelatin and glycerol or sucrose and Arabic gum in matter；And it is closing It include the collutory of active constituent in suitable liquid-carrier.
The compound of the present invention can be prepared for applying with suppository form.It can be first by low melt wax such as fatty acid glycerine Ester admixture or cocoa butter fusing, and active constituent is for example dispersed evenly by stirring.Then by the homogeneous mixture of melting It pours into the mold of suitable size, be allowed to cool and solidify.
The compound of the present invention can be prepared for vaginal application.Also contain carrier known in this field in addition to the active ingredient (s Vaginal plug, tampon, milk agent, gelling agent, paste, foaming agent or spray are suitable.
The compound of the present invention can be prepared for nasal administration.Can by solution or suspension by conventional method, example Such as nasal cavity is directly applied to dropper, suction pipe or sprayer.Preparation can be single dose or multiple dose form.For dropper or suction The multiple dose form of pipe, this can be realized by solution that be suitable for by patient's application, predetermined volume or suspension.For Sprayer, this can for example be realized by metering atomizing pump.
The compound of the present invention can be prepared for aerosol application, especially be applied to respiratory tract and including intranasally applying With.Compound usually has a small granularity, such as the granularity of 5 microns or more decimal magnitude.The granularity can pass through this field Well known method for example passes through micronization acquisition.Active constituent is to contain suitable propellant such as chlorofluorocarbon (CFC) such as dichloro The pressurized package of difluoromethane, trichlorofluoromethane or dichlorotetra-fluoroethane or carbon dioxide or other suitable gas provides.Gas Mist agent can also suitably contain surfactant such as lecithin.Drug dose can be controlled by metering valve.Alternatively, active constituent can With with dry powdered form, for example in suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and The mixture of powders form of compound in polyvinylpyrrolidone provides.Dust carrier will form gel in nasal cavity.Powder Composition can presence can pass through inhalator for example in the form of gelatine capsule agent or cylindrantherae or blister package in a unit By wherein applying powder.
When needing, preparation can be prepared with the enteric coating for being suitable for sustained release or controlled release application active constituent.For example, this The compound of invention can be formulated into transdermal or subcutaneous drug delivery device.When it is necessary to release the compound and work as patient for treatment When the compliance of scheme is most important, these delivery systems are advantageous.Compound in transdermal delivery system is often attached to On skin-adhesive solid support.Compound of interest can also be with penetration enhancer, such as laurocapram (1- dodecane Base azacyclo- hept- 2- ketone) it is applied in combination.It can be inserted subcutaneously into a sustained release delivery system by surgery or injection hypodermic layer.Subcutaneously Compound is encapsulated in liquid soluble membrane, such as silicon rubber or Biodegradable polymeric such as polylactic acid for implantation material.
Pharmaceutical preparation is preferably unit dosage form.In the form, preparation is subdivided into containing appropriate amount active constituent Unit dose.Unit dosage form can be the preparation of packaging kit, the preparation containing discrete magnitude in packaging, such as complete packet The tablet of dress, capsule and powder or ampulla agent in the vial.In addition, unit dosage form can be capsule, tablet, flat Wafer or pastille itself or its any one of these form that can be suitable number in package form.
Other suitable pharmaceutical carriers and their preparation are in Remington:The Science and Practice of Pharmacy 1995Martin, E.W are edited, Mack Publishing Company, and the 19th edition, Easton, It is described in Pennsylvania.
The purposes of the compounds of this invention and pharmaceutical composition
Above compound and pharmaceutical composition provided by the invention, which can be used for preparing, prevents, treats or mitigates Alzheimer The drug of disease can be used for preparation and prevent, treat or mitigate and 5-HT6The drug of receptor related disease.
The feature of pharmaceutical composition of the invention includes shown in formula (I), (I-A), (I-B), (II), (II-A) or (II-B) Compound or the present invention listed by compound and pharmaceutically acceptable carrier, adjuvant or excipient.Group of the invention The amount for closing compound in object can effectively detectably antagonism 5-HT6Receptor is to treat CNS illness, enterogastric diseases and obesity Disease, wherein the CNS illness is ADHD, anxiety, disease relating to mental stress, schizophrenia, besetment and row For obstacle, manic-depressive psychosis, nervous disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea, etc..
" effective quantity " or " effective dose " of the compound of the present invention or pharmaceutically acceptable composition refer to processing or Mitigate the effective quantity that one or more present invention are previously mentioned the severity of illness.According to the method for the present invention, compound and combination Object can be any dosage and any administration route to be efficiently used for handling or mitigate the severity of disease.Required standard True amount will change according to the case where patient, this is depending on ethnic, the age, the general condition of patient, the severity of infection, Special factor, administration mode, etc..Compound or composition can be administered in combination with one or more other therapeutic agents, such as What the present invention was discussed.
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
The general synthetic method of the compounds of this invention
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I), (I-A), (I-B), (II), (II-A) or (II-B).Following reaction Scheme and embodiment are for being further illustrated the contents of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by using in addition to other known examination described in the invention Agent, or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from Shantou Western Gansu Province chemical plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao is risen Imperial chemical reagent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan is dried to obtain by sodium metal reflux.Anhydrous methylene chloride and chloroform are returned by calcium hydride Stream is dried to obtain.Ethyl acetate, n,N-dimethylacetamide and petroleum ether are used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC13、DMSO-d6、CD3OD or acetone-d6It (is reported as unit of ppm) for solvent, with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used: s (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data DEG C) the spectrometer of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Applied to analysis, the source ESI is applied to LC-MS spectrometer.
Low resolution mass spectrometry (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) 6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic sampler and G1315D DAD detector are answered For analyzing, the source ESI is applied to LC-MS spectrometer.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 column, and specification is 2.1 × 30mm, and 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1
Time (min) A(CH3CN, 0.1%HCOOH) B(H2O, 0.1%HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is by 1100 series of high efficiency liquid chromatogram (HPLC) of Agilent come what is evaluated, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of logogram word below is through the present invention:
HCOOH formic acid
HCOH formaldehyde
Cl3CCOCl trichloro-acetic chloride
NH4OAc ammonium acetate
MeCN, CH3CN acetonitrile
CNCH2COOH 2- cyanoacetic acid
CH3NO2Nitromethane
ClSO2OH chlorosulfonic acid
NaBH4Sodium borohydride
LiAlH4Lithium Aluminium Hydride
CH3I iodomethane
CHCl3Chloroform
CDC13Deuterated chloroform
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
DMF N,N-dimethylformamide
The chloro- 5,6- dicyano -1,4- benzoquinones of DDQ 2,3- bis-
(Boc)2O di-tert-butyl dicarbonate
Pd/C palladium/carbon
H2Hydrogen
EtOAc, EA ethyl acetate
MgSO4Magnesium sulfate
MeOH,CH3OH methanol
EtOH ethyl alcohol
CH2Cl2, DCM methylene chloride
ML milliliters
μ L microlitre
PE petroleum ether (60-90 DEG C)
NaOH sodium hydroxide
NaHCO3Sodium bicarbonate
K2CO3Potassium carbonate
KOH potassium hydroxide
Rt retention time
NaBH3CN sodium cyanoborohydride
HCl hydrochloric acid
NaCl sodium chloride
MgCl2Magnesium chloride
NaH sodium hydride
Na2SO4Sodium sulphate
THF tetrahydrofuran
H2O water
Et3N triethylamine
EDTA ethylenediamine tetra-acetic acid
PEI polyethyleneimine
Pargyline Pargyline
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
Following synthetic schemes describes the step of preparation disclosed compound of present invention.Unless otherwise stated, each m, n, k, R1、 R2And R3With definition as described in the present invention.
Synthetic schemes 1
The general synthetic method that the compounds of this invention can be described by synthetic schemes 1 is prepared, and specific steps can join Examine embodiment.Compound (1) react to obtain with cyanoacetic acid compound (2), compound (2) in oxidant (such as DDQ, etc.) Act on lower dehydroaromatizationof obtain compound (3), then compound (3) under the action of reducing agent (such as Lithium Aluminium Hydride, etc.) Obtain compound (4)；Compound (4) under the action of alkali (such as triethylamine, etc.) with 4- methoxyl group -3- (4- (2,2,2- trichlorines Acetyl group) piperazine -1- base) benzene -1- sulfonic acid chloride react to obtain compound (5), then compound (5) alkali (such as potassium hydroxide, Deng) under the action of obtain target product (6).Target product (6) under the action of reducing agent (such as sodium cyanoborohydride, etc.) into One step react to obtain with formaldehyde another target product (7)。
Synthetic schemes 2
The general synthetic method that the compounds of this invention can be described by synthetic schemes 2 is prepared, and specific steps can join Examine embodiment.Compound (1-a) react to obtain with cyanoacetic acid compound (2-a), compound (2-a) oxidant (such as DDQ, etc.) under the action of dehydroaromatizationof obtain compound (3-a), then compound (3-a) in reducing agent (such as tetrahydro aluminium Lithium, etc.) under the action of obtain compound (4-a)；Compound (4-a) under the action of alkali (such as triethylamine, etc.) with it is substituted Benzene sulfonyl chloride (M-A) reaction obtain compound (5-a), then compound (5-a) under the action of alkali (such as potassium hydroxide, etc.) Obtain target product (6-a).Target product (6-a) under the action of reducing agent (such as sodium cyanoborohydride, etc.) further with Formaldehyde react to obtain another target product (7-a)。
Synthetic schemes 3
The general synthetic method that the compounds of this invention can be described by synthetic schemes 3 is prepared, and specific steps can join Examine embodiment.Compound (1) react to obtain with cyanoacetic acid compound (2), compound (2) in oxidant (such as DDQ, etc.) Act on lower dehydroaromatizationof obtain compound (3), compound (3) anti-with halogenated hydrocarbons under the action of alkali (such as sodium hydride, etc.) Should obtain compound (8)；Compound (8) under the action of reducing agent (such as Lithium Aluminium Hydride, etc.) reduction obtain compound (9), Compound (9) under the action of alkali (such as triethylamine, etc.) with 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- Base) benzene -1- sulfonic acid chloride react to obtain compound (10), then compound (10) under the action of alkali (such as potassium hydroxide, etc.) Obtain target product (11).Target product (11) under the action of reducing agent (such as sodium cyanoborohydride, etc.) further with first Aldehyde reaction obtain another target product (12)。
Synthetic schemes 4
The general synthetic method that the compounds of this invention can be described by synthetic schemes 4 is prepared, and specific steps can join Examine embodiment.Compound (1-a) react to obtain with cyanoacetic acid compound (2-a), compound (2-a) oxidant (such as DDQ, etc.) under the action of dehydroaromatizationof obtain compound (3-a), compound (3-a) in the effect of alkali (such as sodium hydride, etc.) Lower and halohydrocarbons reaction obtain compound (8-a)；Compound (8-a) under the action of reducing agent (such as Lithium Aluminium Hydride, etc.) also Original obtain compound (9-a), compound (9-a) under the action of alkali (such as triethylamine, etc.) with substituted benzene sulfonyl chloride (M-A) Reaction obtain compound (10-a), then compound (10-a) obtain target under the action of alkali (such as potassium hydroxide, etc.) and produce Object (11-a).Target product (11-a) further reacted with formaldehyde under the action of reducing agent (such as sodium cyanoborohydride, etc.) Obtain another target product (12-a)。
Synthetic schemes 5
The general synthetic method that the compounds of this invention can be described by synthetic schemes 5 is prepared, and specific steps can join Examine embodiment.Compound (13) with nitromethane act on obtaining compound (14), compound (14) in reducing agent (such as tetrahydro aluminium Lithium, etc.) under the action of reduction obtain compound (15)；Compound (15) under the action of alkali (such as triethylamine, etc.) with 4- first Oxygroup -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride react to obtain compound (16), then chemical combination Object (16) obtained under the action of alkali (such as potassium hydroxide, etc.) target product (17).Target product (17) reducing agent (such as Sodium cyanoborohydride, etc.) under the action of further react to obtain with formaldehyde another target product (18)。
Synthetic schemes 6
The general synthetic method that the compounds of this invention can be described by synthetic schemes 6 is prepared, and specific steps can join Examine embodiment.Compound (13-a) with nitromethane act on obtaining compound (14-a), compound (14-a) reducing agent (such as Lithium Aluminium Hydride, etc.) under the action of reduction obtain compound (15-a)；Compound (15-a) in the work of alkali (such as triethylamine, etc.) With it is lower with replace benzene sulfonyl chloride (M-A) reaction obtain compound (16-a), then compound (16-a) in alkali (such as hydroxide Potassium, etc.) under the action of obtain target product (17-a).Target product (17-a) reducing agent (such as sodium cyanoborohydride, etc.) Under the action of further react to obtain with formaldehyde another target product (18-a)。
Synthetic schemes 7
The general synthetic method that the compounds of this invention can be described by synthetic schemes 7 is prepared, and specific steps can join Examine embodiment.Compound (19) react under the action of alkali (such as potassium carbonate, etc.) with piperazine to obtain compound (20), compound (20) and (Boc)2O react to obtain compound (21)；Compound (21) react to obtain with nitromethane compound (22), then change Conjunction object (22) obtained under the action of sodium borohydride compound (23)；Compound (23) by reduction after obtain compound (24), Compound (24) with replace benzene sulfonyl chloride (M-B) reaction obtain compound (25), then compound (25) by being deprotected To target product (26)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
The synthesis of 1 4- methoxyl group-N- of embodiment (2- (naphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide
The synthesis of the chloro- 1- of step 1) 2,2,2- tri- (4- (2- methoxyphenyl) piperazine -1- base) ethyl ketone
By 1- (2- methoxyphenyl) piperazine hydrochloride (1.0g, 4.39mmol) and triethylamine (2.5mL, 17.70mmol) It is added in methylene chloride (15mL), then under 0 DEG C of low temperature is bathed, trichloro-acetic chloride is slowly added dropwise in Xiang Shangshu mixed liquor (1.0mL, 8.96mmol) after being added dropwise, reaction solution is transferred at 25 DEG C and is reacted 24 hours.Then into reaction mixture It is added methylene chloride (50mL), and is washed with saturated sodium bicarbonate solution (40mL).After liquid separation, organic phase is dry with anhydrous sodium sulfate Dry, filtering, filtrate decompression is spin-dried for obtaining crude product.Crude by column chromatography purifies (petrol ether/ethyl acetate (v/v)=10/1) After obtain title compound be faint yellow solid (763mg, 52%).
MS(ESI,pos.ion)m/z:337.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.09-7.06(m,1H),6.96-6.91(m,3H),4.03(brs, 4H), 3.91 (s, 3H), 3.18 (t, J=4.4Hz, 4H)
The synthesis of step 2) 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride
The chloro- 1- of 2,2,2- tri- (4- (2- methoxyphenyl) piperazine -1- base) ethyl ketone (550mg, 1.63mmol) is dissolved in two In chloromethanes (5mL), then under 0 DEG C of low temperature is bathed, above-mentioned solution is added drop-wise in chlorosulfonic acid (3mL), it, will after reaction 1 hour Reaction solution is poured into the mixed liquor of ice water (30mL) and methylene chloride (50mL), and is vigorously stirred.After liquid separation, organic phase nothing Water magnesium sulfate dries, filters, then filtrate is depressurized and spin-dried i.e. obtain title compound be faint yellow solid (548mg, 78.5%).
MS(ESI,pos.ion)m/z:435.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.75 (dd, J=8.8,2.4Hz, 1H), 7.47 (d, J=2.4Hz, 1H), 7.01 (d, J=8.8Hz, 1H), 4.00 (brs, 7H), 3.21 (t, J=4.8Hz, 4H)
The synthesis of step 3) 2- (3,4- dihydronaphthalene -1- base) acetonitrile
By 3,4- dihydronaphthalene -1 (2H) -one (4g, 24.4mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol) and benzylamine (0.67mL, 6.1mmol) are added sequentially in toluene (30mL), then under 135 DEG C of oil baths React 36h.After reaction, reaction mixture is cooled to 25 DEG C, and ethyl acetate (60mL) dilution is added thereto, then Successively with potassium hydroxide solution (0.5mmol/mL, 40mL), saturated sodium bicarbonate solution (40mL) and saturated salt solution (40mL) Washing.After liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate decompression is spin-dried for obtaining crude product.Crude by column chromatography It is faint yellow solid (1.73g, 42%) that title compound is obtained after purifying (petrol ether/ethyl acetate (v/v)=60/1).
MS(ESI,pos.ion)m/z:170.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.59 (d, J=7.9Hz, 1H), 7.36 (td, J=7.5,1.1Hz, 1H), 7.22 (t, J=7.3Hz, 2H), 5.76 (s, 1H), 2.96-2.87 (m, 4H), 2.02-1.93 (m, 2H)
The synthesis of step 4) 2- (naphthalene -1- base) acetonitrile
2- (3,4- dihydronaphthalene -1- base) acetonitrile (1.69g, 10.0mmol) and DDQ (2.986g, 13.16mmol) are added Into 1,2- dichloroethanes (30mL), then reacted for 24 hours under 100 DEG C of oil baths.After stopping reaction, reaction mixture is cooled to 25 DEG C, and ethyl acetate (60mL) dilution is added thereto, then the reaction mixture after dilution is filtered, filtrate is successively with full It is washed with sodium bicarbonate solution (40mL) and saturated salt solution (40mL).After liquid separation, organic phase is dry with anhydrous sodium sulfate, mistake Filter, filtrate decompression are spin-dried for obtaining crude product.Crude by column chromatography obtains after purifying (petrol ether/ethyl acetate (v/v)=60/1) It is pale white solid (1.5g, 90%) to title compound.
1H NMR(400MHz,CDCl3)δ(ppm):7.94-7.90(m,1H),7.87(s,1H),7.85(s,1H),7.64- 7.54(m,3H),7.50-7.45(m,1H),4.10(s,2H).
The synthesis of step 5) 2- (naphthalene -1- base) ethamine
At 0 DEG C, 2- (naphthalene -1- base) acetonitrile (835mg, 5.0mmol) is added in tetrahydrofuran (25.0mL), then It is slowly added to LiAlH4(950mg, 25.0mmol), ten minutes later, reaction solution is warming up to 25 DEG C, continues to be stirred to react for 24 hours for reaction. After reaction, H is sequentially added into reaction mixture2O(1.24g,1.3g/g LiAlH4), 15%NaOH solution (1.24g, 1.3g/g LiAlH4) and H2O(3.09g,3.25g/g LiAlH4) quenching reaction, add ethyl acetate (30mL).Then right Said mixture is filtered, and filtrate is washed with saturated sodium chloride solution (40mL).After liquid separation, organic phase is dry with anhydrous sodium sulfate Dry, filtering, filtrate decompression is spin-dried for obtaining crude product.After crude by column chromatography purifies (methylene chloride/methanol (v/v)=20/1) Obtaining title compound is yellow oil (274mg, 32%).
MS(ESI,pos.ion)m/z:172.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.05 (d, J=8.1Hz, 1H), 7.88-7.83 (m, 1H), 7.73 (d, J=8.1Hz, 1H), 7.54-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.34 (d, J=6.2Hz, 1H), 3.26 (t, J= 7.0Hz, 2H), 3.12 (t, J=7.0Hz, 2H)
Step 6) 4- methoxyl group-N- (2- (naphthalene -1- base) ethyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) The synthesis of benzsulfamide
At 0 DEG C, 2- (naphthalene -1- base) ethamine (171mg, 1.0mmol) and triethylamine (283 μ L, 2.0mmol) are added to In methylene chloride (8.0mL), it is then slow added into 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene - 1- sulfonic acid chloride (523mg, 1.2mmol), after ten minutes, reaction solution is warming up to 25 DEG C for reaction, and the reaction was continued overnight.Reaction terminates Afterwards, methylene chloride (40mL) is added into reaction mixture, and is washed with saturated sodium chloride solution (40mL).It is organic after liquid separation It is mutually dried, filtered with anhydrous sodium sulfate, filtrate decompression is spin-dried for obtaining crude product.Crude by column chromatography purifies (petroleum ether/acetic acid Ethyl ester (v/v)=1/1) after obtain title compound be white solid (354mg, 62%).
MS(ESI,pos.ion)m/z:570.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.91-7.86 (m, 2H), 7.76 (d, J=8.2Hz, 1H), 7.51- 7.49 (m, 3H), 7.41-7.37 (m, 1H), 7.28-7.27 (m, 2H), 6.88 (d, J=8.6Hz, 1H), 3.94 (brs, 7H), 3.34 (t, J=5.9Hz, 2H), 3.29 (t, J=5.2Hz, 2H), 3.09 (t, J=4.8Hz, 4H)
The synthesis of step 7) 4- methoxyl group-N- (2- (naphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide
At 25 DEG C, by 4- methoxyl group-N- (2- (naphthalene -1- base) ethyl) -3- (4- (2,2,2- trichloroacetyl) piperazine - 1- yl) benzsulfamide (286mg, 0.5mmol) is dissolved in tetrahydrofuran (15mL), be then slowly added into potassium hydroxide (84mg, 1.5mmol is made into 1mmol/mL aqueous solution).After reaction 24 hours, methylene chloride (50mL) is added into reaction mixture, so It is washed afterwards with saturated sodium chloride solution (40mL).After liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate decompression is revolved It is dry to obtain crude product.It is white that title compound is obtained after crude by column chromatography purifying (methylene chloride/methanol (v/v)=20/1) Color solid (191mg, 90%).
MS(ESI,pos.ion)m/z:426.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.90 (t, J=4.6Hz, 1H), 7.84 (t, J=4.6Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 7.48-7.46 (m, 3H), 7.38-7.35 (m, 2H), 7.26 (t, J=7.1Hz, 1H), 6.83 (d, J=8.6Hz, 1H), 3.89 (s, 3H), 3.31-3.30 (m, 2H), 3.28-3.26 (m, 2H), 3.09 (brs, 4H), 3.07 (brs,4H)；
13C NMR(100MHz,CDCl3)δ(ppm):155.4,141.7,133.9,133.8,131.7,131.6,128.8, 127.5,126.9,126.2,125.7,125.4,123.3,122.8,116.8,110.6,55.8,50.5,45.2,43.5, 33.2.
The conjunction of embodiment 2 4- methoxyl group -3- (4- methylpiperazine-1-yl)-N- (2- (naphthalene -1- base) ethyl) benzsulfamide At
By 4- methoxyl group-N- (2- (naphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide (170mg, 0.40mmol) It is dissolved in methanol (5mL), and two drop acetic acid is added.Then at 0 DEG C, sodium cyanoborohydride is slowly added in Xiang Shangshu solution (76mg, 1.2mmol) and formaldehyde (40%, 0.109mL, 1.38mmol).Reaction solution reacts after ten minutes, is warming up to 25 DEG C of continuation Reaction 5 hours.After reaction, water (10mL) is added into reaction mixture and sodium carbonate (212mg, 2.0mmol) is quenched instead It answers, is then extracted with methylene chloride (50mL x 3).Merge organic phase, and is dried, filtered with anhydrous sodium sulfate, filtrate decompression rotation It is dry to obtain crude product.It is white that title compound is obtained after crude by column chromatography purifying (methylene chloride/methanol (v/v)=20/1) Color solid (142mg, 81%).
MS(ESI,pos.ion)m/z:440.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.91 (t, J=4.8Hz, 1H), 7.87-7.85 (m, 1H), 7.75 (d, J=8.2Hz, 1H), 7.52-7.45 (m, 3H), 7.39 (dd, J=8.1,7.0Hz, 1H), 7.34 (d, J=2.2Hz, 1H), 7.25 (d, J=6.6Hz, 1H), 6.85 (d, J=8.6Hz, 1H), 3.92 (s, 3H), 3.38-3.33 (m, 2H), 3.29-3.25 (m,2H),3.09(brs,4H),2.62(brs,4H),2.37(s,3H)；
13C NMR(100MHz,CDCl3)δ(ppm):155.4,141.7,133.9,133.7,131.7,131.6,128.8, 127.6,127.0,126.2,125.7,125.4,123.2,122.5,116.6,110.6,55.8,55.0,50.2,46.0, 43.4,33.2.
3 4- methoxyl group-N- of embodiment (2- (5- methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide Synthesis
The synthesis of step 1) 2- (5- methoxyl group -3,4- dihydronaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by methoxyl group -3 5-, 4- dihydronaphthalene -1 (2H) -one (4g, 22.7mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol) Crude product is prepared in reaction in (30mL) in toluene with benzylamine (0.67mL, 6.1mmol), and crude product is pure through silica gel column chromatography Change (petrol ether/ethyl acetate (v/v)=60/1), it is white solid (1.9g, 42%) that title compound is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:200.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.20 (t, J=8.0Hz, 1H), 6.85 (d, J=8.2Hz, 1H), 6.76 (d, J=7.8Hz, 1H), 6.27 (t, J=4.6Hz, 1H), 3.85 (s, 3H), 3.47 (dd, J=3.4,1.7Hz, 2H), 2.80 (t, J=8.3Hz, 2H), 2.35-2.30 (m, 2H)
The synthesis of step 2) 2- (5- methoxynaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., at 25 DEG C, by 2- (5- methoxyl group -3,4- dihydronaphthalene -1- base) acetonitrile (1.78g, 9.0mmol) and DDQ (2.45g, 10.8mmol) are in methylene chloride Crude product is prepared in reaction in (30mL), and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/ 1) it is white solid (1.36g, 77%) that title compound, is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:198.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.32 (d, J=8.5Hz, 1H), 7.61 (dd, J=7.0,0.9Hz, 1H), 7.51 (dd, J=15.4,7.6Hz, 1H), 7.46-7.41 (m, 2H), 6.90 (d, J=7.6Hz, 1H), 4.11 (s, 2H), 4.02(s,3H).
The synthesis of step 3) 2- (5- methoxynaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 2- (5- methoxynaphthalene -1- base) acetonitrile (985mg, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reaction in THF (25mL) Crude product is prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), after concentrate drying It is colorless oil (553mg, 55%) to title compound.
MS(ESI,pos.ion)m/z:202.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.20 (d, J=8.2Hz, 1H), 7.62 (d, J=8.6Hz, 1H), 7.43 (d, J=7.9Hz, 1H), 7.40-7.35 (m, 2H), 6.83 (d, J=7.6Hz, 1H), 4.00 (s, 3H), 3.20 (t, J= 6.8Hz, 2H), 3.09 (t, J=6.8Hz, 2H)
Step 4) 4- methoxyl group-N- (2- (5- methoxynaphthalene -1- base) ethyl) -3- (4- (2,2,2- trichloroacetyl) piperazine Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (5- methoxyl group Naphthalene -1- base) ethamine (201mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulphur Thick production is prepared in the reaction in methylene chloride (6mL) of acyl chlorides (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) Object, crude product are purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtain title compound after concentrate drying For faint yellow solid (403mg, 67%).
MS(ESI,pos.ion)m/z:600.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.21 (d, J=8.4Hz, 1H), 7.49-7.45 (m, 2H), 7.41- 7.35 (m, 2H), 7.28-7.25 (m, 2H), 6.87 (d, J=8.6Hz, 1H), 6.84 (d, J=7.4Hz, 1H), 4.02-3.94 (m, 10H), 3.32 (t, J=6.1Hz, 2H), 3.25 (t, J=6.7Hz, 2H), 3.09 (t, J=4.8Hz, 4H)
The conjunction of step 5) 4- methoxyl group-N- (2- (5- methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide At
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 4- methoxyl group-N- (2- (5- methoxynaphthalene -1- base) ethyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (300mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (175mg, 77%).
MS(ESI,pos.ion)m/z:456.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.18 (d, J=8.4Hz, 1H), 7.47-7.44 (m, 2H), 7.40- 7.33 (m, 3H), 7.28-7.24 (m, 1H), 6.82 (dd, J=8.5,6.8Hz, 2H), 3.99 (s, 3H), 3.89 (s, 3H), 3.31 (t, J=6.5Hz, 2H), 3.23 (t, J=6.6Hz, 2H), 3.10 (t, J=4.9Hz, 4H), 3.05 (t, J=4.2Hz, 4H)；
13C NMR(100MHz,CDCl3)δ(ppm):155.9,155.4,141.8,133.4,132.6,131.6,127.6, 126.2,126.0,124.7,122.7,121.3,116.8,115.5,110.6,103.7,55.9,55.5,50.9,45.6, 43.5,33.5.
4 4- methoxyl group-N- of embodiment (2- (5- methoxynaphthalene -1- base) ethyl) -3- (4- methylpiperazine-1-yl) benzene sulphur The synthesis of amide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by 4- methoxyl group-N- (2- (5- Methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide (136mg, 0.3mmol), sodium cyanoborohydride (57mg, 0.9mmol) and crude product, crude product warp is prepared in formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL) Silica gel column chromatography purifies (methylene chloride/methanol (v/v)=50/1), and it is white solid that title compound is obtained after concentrate drying (137mg, 97%).
MS(ESI,pos.ion)m/z:470.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.20 (d, J=8.4Hz, 1H), 7.48-7.42 (m, 3H), 7.40- 7.35 (m, 2H), 7.32 (d, J=2.0Hz, 1H), 7.25 (d, J=6.8Hz, 1H), 6.85-6.82 (m, 2H), 4.01 (s, 3H),3.91(s,3H),3.34-3.33(m,4H),3.25-3.21(m,4H),3.08(brs,4H),2.36(s,3H)；
13C NMR(100MHz,CDCl3)δ(ppm):155.9,155.4,141.6,133.3,132.6,131.6,127.6, 126.2,126.0,124.7,122.4,121.3,116.6,115.5,110.6,103.7,55.8,55.5,55.0,50.1, 46.0,43.4,33.5.
The synthesis of 5 N- of embodiment (2- (6- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide
The synthesis of step 1) 2- (the fluoro- 3,4- dihydronaphthalene -1- base of 6-) acetonitrile
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by fluoro- 3, the 4- bis- of 6- Hydrogen naphthalene -1 (2H) -one (4g, 24.4mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol) and benzyl Crude product is prepared in reaction to amine (0.67mL, 6.1mmol) in (30mL) in toluene, and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), it is white solid (4.1g, 90%) that title compound is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:188.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.07 (dd, J=8.0,5.6Hz, 1H), 6.93-6.89 (m, 2H), 6.21 (t, J=4.8Hz, 1H), 3.46 (dd, J=3.2,1.6Hz, 2H), 2.79 (t, J=8.0Hz, 2H), 2.37-2.32 (m, 2H).
The synthesis of step 2) 2- (6- fluoronaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (6- fluoro- 3,4- Dihydronaphthalene -1- base) acetonitrile (1.87g, 10.0mmol) and DDQ (2.72g, 12.0mmol) be anti-in 1,2- dichloroethanes (30mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), is concentrated and dried After obtain title compound be white solid (666mg, 36%).
MS(ESI,pos.ion)m/z:186.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.87 (dd, J=9.2,5.2Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.56-7.47 (m, 3H), 7.38 (td, J=8.4,2.8Hz, 1H), 4.11 (s, 2H)
The synthesis of step 3) 2- (6- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1- Base) acetonitrile (925mg, 5.0mmol) and LiAlH4Thick production is prepared in (950mg, 25.0mmol) reaction in THF (25mL) Object, crude product are purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), obtain title compound after concentrate drying For colorless oil (463mg, 49%).
MS(ESI,pos.ion)m/z:190.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.04 (dd, J=9.2,5.6Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.47-7.40 (m, 2H), 7.30-7.26 (m, 2H), 3.22 (t, J=6.8Hz, 2H), 3.09 (t, J=6.8Hz, 2H)
Step 4) N- (2- (6- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- Base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1- Base) ethamine (190mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride Crude product is prepared in the reaction in methylene chloride (6mL) of (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol), slightly Product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), and it is light that title compound is obtained after concentrate drying Yellow solid (499mg, 84.8%).
MS(ESI,pos.ion)m/z:588.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.88 (dd, J=9.2,5.2Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.47-7.43 (m, 2H), 7.38 (t, J=7.6Hz, 1H), 7.28-7.27 (m, 1H), 7.25-7.20 (m, 2H), 6.86 (d, J=8.4Hz, 1H), 4.09-3.87 (m, 7H), 3.33-3.29 (m, 2H), 3.25 (t, J=6.0Hz, 2H), 3.09 (t, J =4.8Hz, 4H)
The synthesis of step 5) N- (2- (6- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- (2- (6- fluorine Naphthalene -1- base) ethyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (295mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (220mg, 99.6%).
MS(ESI,pos.ion)m/z:444.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.88 (dd, J=9.2,5.6Hz, 1H), 7.64 (t, J=7.2Hz, 1H), 7.46-7.39 (m, 2H), 7.37-7.33 (m, 2H), 7.25-7.18 (m, 2H), 6.82 (dd, J=8.8,6.0Hz, 1H), 3.88(s,3H),3.31-3.21(m,4H),3.10-3.04(m,8H),2.69(s,1H)；
13C NMR(100MHz,CDCl3)δ(ppm):160.3(d,JC-F=245.0Hz), 155.5,142.0,134.8 (d, JC-F=9.0Hz), 134.2,131.5,128.6,126.9 (d, JC-F=5.0Hz), 126.7,126.2,125.9 (d, JC-F= 9.0Hz),122.6,116.7,116.4(d,JC-F=24.8Hz), 111.7 (d, JC-F=19.8Hz), 110.6,55.8,51.2, 45.8,43.5,33.3.
6 N- of embodiment (2- (6- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) benzsulfamide Synthesis
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- (2- (6- fluoronaphthalene -1- Base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (133mg, 0.3mmol), sodium cyanoborohydride (57mg, 0.9mmol) and crude product, crude product warp is prepared in formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL) Silica gel column chromatography purifies (methylene chloride/methanol (v/v)=30/1), and it is white solid that title compound is obtained after concentrate drying (124mg, 90.6%).
MS(ESI,pos.ion)m/z:458.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.88 (dd, J=9.6,5.6Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.44-7.41 (m, 2H), 7.36 (t, J=7.6Hz, 1H), 7.31 (d, J=2.9Hz, 1H), 7.26-7.21 (m, 1H), 7.18 (d, J=6.8Hz, 1H), 6.82 (d, J=8.8Hz, 1H), 3.89 (s, 3H), 3.31-3.27 (m, 2H), 3.24-3.20 (m,2H),3.07(brs,4H),2.61(brs,4H),2.35(s,3H)；
13C NMR(100MHz,CDCl3)δ(ppm):160.3(d,JC-F=245.0Hz), 155.4,141.6,134.8 (d, JC-F=9.0Hz), 134.2,131.6,128.6,126.9 (d, JC-F=5.1Hz), 126.7,126.2 (d, JC-F=2.3Hz), 125.9(d,JC-F=8.8Hz), 122.5,116.6,116.4 (d, JC-F=24.7Hz), 111.7 (d, JC-F=19.8Hz), 110.6,55.8,55.0,50.1,45.9,43.5,33.4.
7 4- methoxyl group-N- of embodiment (2- (7- methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide Synthesis
Step 1) 4- methoxyl group-N- (2- (7- methoxynaphthalene -1- base) ethyl) -3- (4- (2,2,2- trichloroacetyl) piperazine Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (7- methoxyl group Naphthalene -1- base) ethamine (201mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulphur Thick production is prepared in the reaction in methylene chloride (6mL) of acyl chlorides (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) Object, crude product are purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtain title compound after concentrate drying For faint yellow solid (510mg, 84.8%).
MS(ESI,pos.ion)m/z:600.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.74 (d, J=8.9Hz, 1H), 7.66 (d, J=7.3Hz, 1H), 7.45 (dd, J=8.5,2.2Hz, 1H), 7.25-7.19 (m, 4H), 7.14 (dd, J=8.9,2.4Hz, 1H), 6.85 (d, J= 8.6Hz,1H),3.99(brs,4H),3.93(s,3H),3.92(s,3H),3.34-3.30(m,2H),3.25-3.22(m,2H), 3.06(brs,4H).
The conjunction of step 2) 4- methoxyl group-N- (2- (7- methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide At
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 4- methoxyl group-N- (2- (7- methoxynaphthalene -1- base) ethyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (300mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (214mg, 94%).
MS(ESI,pos.ion)m/z:456.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.75 (d, J=8.7Hz, 1H), 7.68 (d, J=7.4Hz, 1H), 7.43 (dd, J=8.3,2.0Hz, 1H), 7.25-7.19 (m, 4H), 7.12 (dd, J=8.7,2.4Hz, 1H), 6.86 (d, J= 8.6Hz,1H),3.94(s,3H),3.92(s,3H),3.35-3.30(m,2H),3.26-3.22(m,2H),3.06-3.01(m, 4H),2.65-2.62(m,4H).
8 4- methoxyl group-N- of embodiment (2- (7- methoxynaphthalene -1- base) ethyl) -3- (4- methylpiperazine-1-yl) benzene sulphur The synthesis of amide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by 4- methoxyl group-N- (2- (7- Methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide (137mg, 0.3mmol), sodium cyanoborohydride (57mg, 0.9mmol) and crude product, crude product warp is prepared in formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL) Silica gel column chromatography purifies (methylene chloride/methanol (v/v)=30/1), and it is white solid that title compound is obtained after concentrate drying (120mg, 85%).
MS(ESI,pos.ion)m/z:470.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.75 (d, J=8.9Hz, 1H), 7.67 (d, J=7.9Hz, 1H), 7.45 (dd, J=8.5,2.2Hz, 1H), 7.32 (d, J=2.2Hz, 1H), 7.28 (d, J=2.2Hz, 1H), 7.26-7.19 (m, 2H), 7.16 (dd, J=8.9,2.4Hz, 1H), 6.83 (d, J=8.6Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.34- 3.32 (m, 2H), 3.25 (t, J=7.1Hz, 2H), 3.07 (brs, 4H), 2.60 (brs, 4H), 2.35 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):158.0,155.5,141.8,132.9,132.5,131.8,130.4, 129.3,127.4,127.3,123.2,122.4,118.3,116.6,110.7,102.1,55.8,55.5,55.0,50.2, 46.0,43.3,33.8.
The synthesis of 9 N- of embodiment (2- (7- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide
The synthesis of step 1) 2- (the fluoro- 3,4- dihydronaphthalene -1- base of 7-) acetonitrile
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by fluoro- 3, the 4- bis- of 7- Hydrogen naphthalene -1 (2H) -one (4g, 24.4mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol) and benzyl Crude product is prepared in reaction to amine (0.67mL, 6.1mmol) in (30mL) in toluene, and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), obtained after concentrate drying title compound be faint yellow solid (3.88g, 85%).
1H NMR(400MHz,CDCl3) δ (ppm): 7.15 (dd, J=8.2,5.8Hz, 1H), 6.92 (td, J=8.4, 2.5Hz, 1H), 6.83 (dd, J=9.9,2.5Hz, 1H), 6.36 (t, J=4.2Hz, 1H), 3.47 (dd, J=3.4,1.7Hz, 2H), 2.78 (t, J=8.1Hz, 2H), 2.41-2.36 (m, 2H)
The synthesis of step 2) 2- (7- fluoronaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- fluoro- 3,4- Dihydronaphthalene -1- base) acetonitrile (1.87g, 10.0mmol) and DDQ (2.72g, 12.0mmol) be anti-in 1,2- dichloroethanes (30mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), is concentrated and dried After obtain title compound be white solid (980mg, 53%).
MS(ESI,pos.ion)m/z:186.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.94 (dd, J=9.0,5.8Hz, 1H), 7.88 (d, J=8.3Hz, 1H), 7.66 (d, J=7.1Hz, 1H), 7.53-7.44 (m, 2H), 7.40-7.32 (m, 1H), 4.10 (s, 2H)
The synthesis of step 3) 2- (7- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1- Base) acetonitrile (925mg, 5.0mmol) and LiAlH4Thick production is prepared in (950mg, 25.0mmol) reaction in THF (25mL) Object, crude product are purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), obtain title compound after concentrate drying For light yellow oil (522mg, 55%).
MS(ESI,pos.ion)m/z:190.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.86 (dd, J=9.0,5.9Hz, 1H), 7.74 (dd, J=6.1, 3.4Hz, 1H), 7.66 (dd, J=11.2,2.3Hz, 1H), 7.41-7.36 (m, 2H), 7.28-7.24 (m, 1H), 3.23 (t, J =6.4Hz, 2H), 3.19-3.11 (m, 2H)
Step 4) N- (2- (7- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- Base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1- Base) ethamine (189mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride Crude product is prepared in the reaction in methylene chloride (6mL) of (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol), slightly Product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), and it is light that title compound is obtained after concentrate drying Yellow solid (495mg, 84%).
MS(ESI,pos.ion)m/z:588.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.85 (dd, J=9.0,5.9Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.54 (dd, J=8.5,2.2Hz, 1H), 7.46 (dd, J=11.1,2.3Hz, 1H), 7.37-7.22 (m, 4H), 6.91 (d, J=8.6Hz, 1H), 3.95 (brs, 7H), 3.33-3.28 (m, 2H), 3.20 (t, J=7.1Hz, 2H), 3.12 (brs, 4H).
The synthesis of step 5) N- (2- (7- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- (2- (7- fluorine Naphthalene -1- base) ethyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (295mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (193mg, 87%).
MS(ESI,pos.ion)m/z:444.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.86 (dd, J=8.7,5.4Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.54 (dd, J=8.4,2.0Hz, 1H), 7.46 (dd, J=11.2,2.4Hz, 1H), 7.38-7.23 (m, 4H), 6.92 (d, J=8.2Hz, 1H), 3.95 (s, 3H), 3.33-3.28 (m, 2H), 3.22-3.18 (m, 2H), 3.12 (brs, 4H), 2.72 (brs,4H).
10 N- of embodiment (2- (7- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) benzsulfamide Synthesis
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- (2- (7- fluoronaphthalene -1- Base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (133mg, 0.3mmol), sodium cyanoborohydride (57mg, 0.9mmol) and crude product, crude product warp is prepared in formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL) Silica gel column chromatography purifies (methylene chloride/methanol (v/v)=30/1), and it is white solid that title compound is obtained after concentrate drying (126mg, 92%).
MS(ESI,pos.ion)m/z:458.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.78 (dd, J=8.9,6.0Hz, 1H), 7.67 (d, J=8.1Hz, 1H), 7.51 (dd, J=8.5,1.9Hz, 1H), 7.46 (dd, J=11.0,1.7Hz, 1H), 7.38 (d, J=1.9Hz, 1H), 7.29 (dd, J=10.6,4.3Hz, 1H), 7.25 (d, J=6.8Hz, 1H), 7.21 (td, J=8.7,2.2Hz, 1H), 6.85 (d, J=8.6Hz, 1H), 3.88 (s, 3H), 3.27-3.25 (m, 2H), 3.15 (t, J=7.3Hz, 2H), 3.08 (brs, 4H), 2.59(brs,4H),2.32(s,3H)；
13C NMR(150MHz,CDCl3) δ (ppm): 160.8 (d, J=244.5Hz), 155.5,141.7,133.6 (d, J =4.5Hz), 132.6 (d, J=7.5Hz), 131.7,131.2 (d, J=9.0Hz), 130.8,127.8,127.3,124.8 (d, ), J=2.1Hz 122.6,116.7,115.9 (d, J=25.5Hz), 110.8,107.1 (d, J=21.0Hz), 55.8,55.0, 50.1,45.9,43.3,33.3.
The synthesis of 11 N- of embodiment (2- (7- bromonaphthalene -1- base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide
The synthesis of step 1) 2- (the bromo- 3,4- dihydronaphthalene -1- base of 7-) acetonitrile
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by bromo- 3, the 4- bis- of 7- Hydrogen naphthalene -1 (2H) -one (4g, 17.8mmol), 2- cyanoacetic acid (3.1g, 36.6mmol), enanthic acid (794mg, 6.1mmol) and benzyl Crude product is prepared in reaction to amine (0.67mL, 6.1mmol) in (30mL) in toluene, and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), it is white solid (4.2g, 95%) that title compound is obtained after concentrate drying.
1H NMR(400MHz,CDCl3) δ (ppm): 7.32 (dd, J=8.0,1.9Hz, 1H), 7.19 (d, J=1.8Hz, 1H), 7.05 (d, J=8.0Hz, 1H), 6.33 (dd, J=3.7,2.3Hz, 1H), 3.45 (dd, J=3.4,1.7Hz, 2H), 2.74 (t, J=8.1Hz, 2H), 2.36 (tdd, J=7.8,4.4,2.1Hz, 2H)
The synthesis of step 2) 2- (7- bromonaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (7- bromo- 3,4- Dihydronaphthalene -1- base) acetonitrile (2.48g, 10.0mmol) and DDQ (2.72g, 12.0mmol) be anti-in 1,2- dichloroethanes (30mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), is concentrated and dried After obtain title compound be white solid (1.21g, 49%).
MS(ESI,pos.ion)m/z:245.9[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.00 (d, J=0.7Hz, 1H), 7.82 (d, J=8.3Hz, 1H), 7.77 (d, J=8.7Hz, 1H), 7.63 (ddd, J=6.1,3.9,1.3Hz, 2H), 7.49 (dd, J=8.2,7.2Hz, 1H), 4.09(s,2H).
The synthesis of step 3) 2- (7- bromonaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 2- (7- bromonaphthalene -1- base) acetonitrile (1.2g, 4.9mmol) and LiAlH4(950mg, 25.0mmol) reaction preparation in THF (25mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), is marked after concentrate drying Topic compound is colorless oil (649mg, 53%).MS(ESI,pos.ion)m/z:250.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.19 (d, J=1.5Hz, 1H), 7.71 (t, J=8.7Hz, 2H), 7.55 (dd, J=8.7,1.9Hz, 1H), 7.43-7.40 (m, 1H), 7.37 (d, J=6.0Hz, 1H), 3.19 (t, J=6.6Hz, 2H), 3.10 (t, J=6.6Hz, 2H)
Step 4) N- (2- (7- bromonaphthalene -1- base) ethyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- Base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1- Base) ethamine (250mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride Crude product is prepared in the reaction in methylene chloride (6mL) of (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol), slightly Product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), and it is light that title compound is obtained after concentrate drying Yellow solid (551mg, 84.8%).
MS(ESI,pos.ion)m/z:648.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.03 (s, 1H), 7.71 (d, J=8.7Hz, 1H), 7.70 (d, J= 8.1Hz, 1H), 7.55-7.49 (m, 2H), 7.39 (t, J=7.6Hz, 1H), 7.29 (d, J=6.9Hz, 1H), 7.26 (s, 1H), 6.89 (d, J=8.6Hz, 1H), 3.93 (brs, 7H), 3.29 (t, J=6.3Hz, 2H), 3.21 (t, J=6.9Hz, 2H), 3.08 (t, J=4.5Hz, 4H)
The synthesis of step 5) N- (2- (7- bromonaphthalene -1- base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- (2- (7- bromine Naphthalene -1- base) ethyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (325mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (211mg, 84%).
MS(ESI,pos.ion)m/z:504.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.07 (s, 1H), 7.69 (dd, J=8.7,5.2Hz, 2H), 7.53 (dt, J=8.5,2.2Hz, 2H), 7.40-7.36 (m, 2H), 7.29 (d, J=5.6Hz, 1H), 6.88 (d, J=8.6Hz, 1H), 3.91 (s, 3H), 3.29 (t, J=6.5Hz, 2H), 3.21 (t, J=6.7Hz, 2H), 3.14 (brs, 4H), 3.12 (brs, 4H)；
13C NMR(100MHz,CDCl3)δ(ppm):155.5,141.8,133.2,132.8,132.2,131.5,130.5, 129.0,127.9,127.3,125.9,125.7,122.9,120.5,116.8,110.6,103.7,55.8,55.5,50.6, 45.5,43.3,33.1.
12 N- of embodiment (2- (7- bromonaphthalene -1- base) ethyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) benzsulfamide Synthesis
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- (2- (7- bromonaphthalene -1- Base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (151mg, 0.3mmol), sodium cyanoborohydride (57mg, 0.9mmol) and crude product, crude product warp is prepared in formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL) Silica gel column chromatography purifies (methylene chloride/methanol (v/v)=30/1), and it is white solid that title compound is obtained after concentrate drying (151mg, 97%).
MS(ESI,pos.ion)m/z:518.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.05 (s, 1H), 7.71 (s, 1H), 7.69 (t, J=4.0Hz, 1H), 7.53 (dd, J=8.7,1.7Hz, 1H), 7.50 (dd, J=8.5,2.1Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 7.32 (d, J=2.1Hz, 1H), 7.27 (d, J=6.0Hz, 1H), 6.87 (d, J=8.6Hz, 1H), 3.91 (s, 3H), 3.31-3.29 (m, 2H), 3.20 (t, J=7.0Hz, 2H), 3.08 (brs, 4H), 2.60 (brs, 4H), 2.35 (s, 3H)；
13C NMR(100MHz,CDCl3)δ(ppm):155.4,141.7,133.1,132.8,132.2,131.5,130.5, 129.1,128.0,127.4,125.9,125.6,122.5,120.5,116.6,110.6,55.8,55.0,50.2,46.0, 43.2,33.1.
13 4- methoxyl group-N- of embodiment (2- methyl -2- (naphthalene -1- base) propyl) -3- (piperazine -1- base) benzsulfamide Synthesis
The synthesis of step 1) 2- methyl -2- (naphthalene -1- base) propionitrile
At -30 DEG C, by 2- (naphthalene -1- base) acetonitrile (1.67g, 10.0mmol) and sodium hydride, (60% is dispersed in mineral oil In, 2.0g, 50.0mmol) it is added in anhydrous DMF (10mL), after being stirred to react 1h, iodomethane is added into reaction solution (5.0mL, 80.0mmol) is then to slowly warm up to react overnight at 65 DEG C.After reaction, it is added into reaction mixture full With saline solution (30mL) quenching reaction, and with ethyl acetate (30mL x 3) extract.Merge organic phase, it is dry with anhydrous sodium sulfate Dry, filtering, filtrate decompression is spin-dried for obtaining crude product.Crude by column chromatography purifies (petrol ether/ethyl acetate (v/v)=50/1) After obtain title compound be faint yellow solid (1.5g, 77%).
MS(ESI,pos.ion)m/z:196.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.57 (d, J=8.7Hz, 1H), 7.93 (d, J=8.2Hz, 1H), 7.86 (d, J=8.1Hz, 1H), 7.64-7.63 (m, 1H), 7.56 (d, J=7.5Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.46 (t, J=7.7Hz, 1H), 1.99 (s, 6H)；
13C NMR(150MHz,CDCl3)δ(ppm):135.7,134.7,130.2,129.6,129.5,126.4,125.8, 125.1,125.0,124.6,122.8,34.7,28.8.
The synthesis of step 2) 2- methyl -2- (naphthalene -1- base) propane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 2- Methyl -2- (naphthalene -1- base) propionitrile (975mg, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reaction in THF (25mL) Crude product is prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), after concentrate drying It is colorless oil (587mg, 59%) to title compound.
MS(ESI,pos.ion)m/z:200.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.40 (d, J=8.5Hz, 1H), 7.93-7.88 (m, 1H), 7.76 (d, J=8.1Hz, 1H), 7.52-7.46 (m, 3H), 7.43 (t, J=7.7Hz, 1H), 3.31 (s, 2H), 1.63 (s, 6H)
Step 3) 4- methoxyl group-N- (2- methyl -2- (naphthalene -1- base) propyl) -3- (4- (2,2,2- trichloroacetyl) piperazine Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- methyl -2- (naphthalene -1- base) propane -1- amine (199mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) The reaction in methylene chloride (6mL) of benzene -1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) is prepared into To crude product, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtains title after concentrate drying Compound is faint yellow solid (395mg, 66%).
MS(ESI,pos.ion)m/z:597.9[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.28 (d, J=8.5Hz, 1H), 7.92 (dd, J=7.9,1.5Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.49-7.43 (m, 4H), 7.41 (t, J=7.7Hz, 1H), 7.38 (dd, J=8.5, 2.2Hz 1H), 7.26 (d, J=2.2Hz, 1H), 7.05 (d, J=8.6Hz, 1H), 3.96-3.76 (m, 7H), 3.18 (d, J= 6.8Hz,2H),3.02(s,4H),1.50(s,6H).
The synthesis of step 4) 4- methoxyl group-N- (2- methyl -2- (naphthalene -1- base) propyl) -3- (piperazine -1- base) benzsulfamide
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 4- methoxyl group-N- (2- methyl -2- (naphthalene -1- base) propyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (300mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (166mg, 73%).
MS(ESI,pos.ion)m/z:454.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.11 (d, J=8.8Hz, 1H), 7.87 (d, J=8.1Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.46 (t, J=6.4Hz, 1H), 7.43 (d, J=8.3Hz, 1H), 7.40 (d, J=7.6Hz, 1H), 7.35 (t, J=7.3Hz, 1H), 7.29 (dd, J=8.6,2.2Hz, 1H), 7.15 (d, J=2.1Hz, 1H), 6.78 (t, J =6.7Hz, 1H), 3.92 (s, 3H), 3.50 (brs, 2H), 3.03 (brs, 4H), 2.93 (brs, 4H), 1.61 (s, 6H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.4,142.0,140.1,135.0,131.2,131.0,129.9, 128.7,125.94,125.3,125.2,125.1,124.9,122.5,116.7,110.5,55.8,52.9,51.5,45.9, 40.0,28.3.
14 4- methoxyl group-N- of embodiment (2- methyl -2- (naphthalene -1- base) propyl) -3- (4- methylpiperazine-1-yl) benzene sulphur The synthesis of amide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by 4- methoxyl group-N- (2- first Base -2- (naphthalene -1- base) propyl) -3- (piperazine -1- base) benzsulfamide (136mg, 0.3mmol), sodium cyanoborohydride (57mg, It 0.9mmol) is prepared with formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL), obtains crude product, crude product It is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), it is white solid that title compound is obtained after concentrate drying (126mg, 90%).
MS(ESI,pos.ion)m/z:468.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.07 (d, J=8.8Hz, 1H), 7.84 (d, J=7.4Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.44-7.40 (m, 2H), 7.37 (t, J=7.7Hz, 1H), 7.33-7.30 (m, 1H), 7.26 (dd, J=8.4,2.2Hz, 1H), 7.13 (d, J=2.2Hz, 1H), 6.75 (d, J=8.5Hz, 1H), 3.89 (s, 3H), 3.47 (s,2H),2.99(brs,4H),2.57(brs,4H),2.34(s,3H),1.58(s,6H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.3,141.6,140.0,134.9,131.1,130.9,129.8, 128.6,125.8,125.2,125.2,125.1,124.9,122.3,116.5,110.5,55.7,55.0,52.8,50.1, 46.0,39.9,28.2.
15 N- of embodiment (2- (6- fluoronaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulfonyl The synthesis of amine
The synthesis of step 1) 2- (6- fluoronaphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 13 step 1 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene- 1- yl) acetonitrile (1.85g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50.0mmol) and iodomethane (5.0mL, 80.0mmol) reaction preparation in anhydrous DMF (10mL), obtains crude product, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), it is yellow solid (1.94g, 91%) that title compound is obtained after concentrate drying.
1H NMR(600MHz,CDCl3) δ (ppm): 8.59 (dd, J=9.5,5.3Hz, 1H), 7.80 (dd, J=7.2, 1.9Hz, 1H), 7.55 (dd, J=9.4,2.7Hz, 1H), 7.51-7.46 (m, 2H), 7.43 (ddd, J=9.5,8.1,2.8Hz, 1H),1.99(s,6H)；
13C NMR(150MHz,CDCl3) δ (ppm): 160.0 (d, J=246Hz), 136.1 (d, J=1.5Hz), 135.9 (d, J=9.0Hz), 128.9 (d, J=4.5Hz), 127.2 (d, J=1.5Hz), 127.1 (d, J=9.0Hz), 126.2, 124.9,122.2 (d, J=3.0Hz), 116.5 (d, J=25.5Hz), 112.5 (d, J=19.5Hz), 34.63,28.9.
The synthesis of step 2) 2- (6- fluoronaphthalene -1- base) -2- methylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 2- (6- fluoronaphthalene -1- base) -2- methyl propionitrile (1.06g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is in THF (25mL) Crude product is prepared in reaction, and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), is concentrated and dried After obtain title compound be colorless oil (705mg, 65%).
MS(ESI,pos.ion)m/z:218.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.98 (dd, J=13.0,2.2Hz, 1H), 7.86 (dd, J=9.0, 6.5Hz, 1H), 7.73 (d, J=8.1Hz, 1H), 7.51 (d, J=7.4Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 7.29- 7.22(m,1H),3.26(s,2H),1.59(s,6H).
Step 3) N- (2- (6- fluoronaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene -1- Base) -2- methylpropane -1- amine (217mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) The reaction in methylene chloride (6mL) of benzene -1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) is prepared into To crude product, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtains title after concentrate drying Compound is faint yellow solid (278mg, 45%).
MS(ESI,pos.ion)m/z:616.0[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.34 (dd, J=9.5,5.5Hz, 1H), 7.79 (d, J=7.5Hz, 1H), 7.70 (dd, J=10.0,2.8Hz, 1H), 7.44 (t, J=7.3Hz, 2H), 7.40 (d, J=6.2Hz, 1H), 7.36 (d, J=2.1Hz, 1H), 7.34 (d, J=2.0Hz, 1H), 7.23 (d, J=2.1Hz, 1H), 7.03 (d, J=8.6Hz, 1H), 4.00-3.76 (m, 7H), 3.18 (d, J=6.7Hz, 2H), 3.03 (brs, 4H), 1.49 (s, 6H)
Step 4) N- (2- (6- fluoronaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide Synthesis
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- (2- (6- fluorine Naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (308mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) are anti-in tetrahydrofuran (20mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying Obtaining title compound is white solid (170mg, 72%).
MS(ESI,pos.ion)m/z:472.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.08 (dd, J=9.5,5.3Hz, 1H), 7.65 (t, J=4.4Hz, 1H), 7.43 (dd, J=9.4,2.5Hz, 1H), 7.38-7.37 (m, 2H), 7.22 (dd, J=8.5,2.0Hz, 1H), 7.13 (d, J=1.9Hz, 1H), 7.10-7.05 (m, 1H), 6.73 (d, J=8.5Hz, 1H), 3.89 (s, 3H), 3.42 (s, 2H), 3.02- 2.93(m,8H),1.56(s,6H)；
13C NMR(150MHz,CDCl3) δ (ppm): 159.4 (d, J=244.5Hz), 155.3,141.8,140.6, 136.2 (d, J=9.0Hz), 131.0,127.9,127.8 (d, J=4.5Hz), 127.6 (d, J=7.5Hz), 126.3, (125.1,122.3,116.6,115.1 d, J=24.0Hz), 112.5 (d, J=19.5Hz), 110.5,55.7,52.851.2, 45.7,39.9,28.2.
16 N- of embodiment (2- (6- fluoronaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) The synthesis of benzsulfamide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- (2- (6- fluoronaphthalene -1- Base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (141mg, 0.3mmol), sodium cyanoborohydride Crude product is prepared in the reaction in methanol (10mL) of (57mg, 0.9mmol) and formaldehyde (40%, 0.026mL, 0.9mmol), slightly Product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and title compound is obtained after concentrate drying as white Solid (109mg, 75%).
MS(ESI,pos.ion)m/z:486.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.07 (dd, J=9.4,5.3Hz, 1H), 7.67 (t, J=4.6Hz, 1H), 7.44 (dd, J=9.4,2.5Hz, 1H), 7.39-7.37 (m, 2H), 7.21 (dd, J=8.3,2.0Hz, 1H), 7.12 (d, J=2.0Hz, 1H), 7.11-7.05 (m, 1H), 6.72 (d, J=8.5Hz, 1H), 3.89 (s, 3H), 3.43 (s, 2H), 3.02- 2.93(m,8H),2.65(s,3H),1.57(s,6H).
17 4- methoxyl group-N- of embodiment (2- (7- methoxynaphthalene -1- base) -2- methyl-propyl) -3- (piperazine -1- base) benzene The synthesis of sulfonamide
The synthesis of step 1) 2- (7- methoxynaphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 13 step 1 of embodiment is prepared, i.e., by 2- (7- methoxyl group Naphthalene -1- base) acetonitrile (1.97g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50.0mmol) and iodomethane Crude product is prepared in (5.0mL, 80.0mmol) reaction in anhydrous DMF (10mL), and crude product is purified by silica gel column chromatography (stone Oily ether/ethyl acetate (v/v)=60/1), it is yellow solid (1.8g, 80%) that title compound is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:226.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.90-7.73 (m, 3H), 7.48 (dd, J=7.4,0.9Hz, 1H), 7.34 (t, J=7.8Hz, 1H), 7.24 (dd, J=9.0,2.4Hz, 1H), 4.03 (s, 3H), 2.00 (s, 6H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.8,134.27,131.3,130.9,130.0,129.2, 124.8,123.2,122.8,118.4,103.8,55.4,34.6,28.6.
The synthesis of step 2) 2- (7- methoxynaphthalene -1- base) -2- methylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 2- (7- methoxynaphthalene -1- base) -2- methyl propionitrile (1.12g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is in THF Crude product is prepared in reaction in (25mL), and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), It is colorless oil (790mg, 69%) that title compound is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:230.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.80 (d, J=8.9Hz, 1H), 7.72-7.69 (m, 2H), 7.47- 7.45 (m, 1H), 7.29-7.28 (m, 1H), 7.17 (dd, J=8.9,2.4Hz, 1H), 3.95 (s, 3H), 3.30 (s, 2H), 1.62(s,6H).
Step 3) 4- methoxyl group-N- (2- (7- methoxynaphthalene -1- base) -2- methyl-propyl) -3- (4- (tri- chloroethene of 2,2,2- Acyl group) piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (7- methoxyl group Naphthalene -1- base) -2- methylpropane -1- amine (230mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine - 1- yl) benzene -1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) the reaction system in methylene chloride (6mL) Standby to obtain crude product, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtains after concentrate drying Title compound is faint yellow solid (434mg, 69%).
MS(ESI,pos.ion)m/z:628.0[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 7.84 (d, J=9.0Hz, 1H), 7.72 (d, J=8.0Hz, 1H), 7.62 (t, J=6.9Hz, 1H), 7.56 (d, J=1.8Hz, 1H), 7.44 (d, J=7.2Hz, 1H), 7.38 (dd, J=8.5, 2.2Hz, 1H), 7.27-7.25 (m, 2H), 7.14 (dd, J=8.9,2.3Hz, 1H), 7.05 (d, J=8.6Hz, 1H), 3.89 (brs, 7H), 3.83 (s, 3H), 3.14 (d, J=6.9Hz, 2H), 3.01 (brs, 4H), 1.52 (s, 6H)
Step 4) 4- methoxyl group-N- (2- (7- methoxynaphthalene -1- base) -2- methyl-propyl) -3- (piperazine -1- base) benzene sulfonyl The synthesis of amine
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 4- methoxyl group-N- (2- (7- methoxynaphthalene -1- base) -2- methyl-propyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (314mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) are anti-in tetrahydrofuran (20mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying Obtaining title compound is white solid (230mg, 95%).
MS(ESI,pos.ion)m/z:484.2[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 7.84 (d, J=9.0Hz, 1H), 7.72 (d, J=8.0Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=1.9Hz, 1H), 7.44 (d, J=7.2Hz, 1H), 7.32 (dd, J=8.5,2.1Hz, 1H), 7.26 (t, J=7.7Hz, 1H), 7.23 (d, J=2.1Hz, 1H), 7.15 (dd, J=8.9,2.3Hz, 1H), 7.00 (d, J= 8.6Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.14 (d, J=4.2Hz, 2H), 2.84 (brs, 8H), 1.52 (s, 6H)；
13C NMR(150MHz,DMSO-d6)δ(ppm):156.7,155.1,142.2,141.1,132.9,132.3, 131.6,130.4,128.1,125.8,123.4,121.7,117.5,116.2,111.7,105.7,56.2,55.6,51.8, 51.2,45.8,40.2,27.4.
18 4- methoxyl group-N- of embodiment (2- (7- methoxynaphthalene -1- base) -2- methyl-propyl) -3- (4- methyl piperazine -1- Base) benzsulfamide synthesis
This step title compound method referring to described in embodiment 2 is prepared, i.e., by 4- methoxyl group-N- (2- (7- Methoxynaphthalene -1- base) -2- methyl-propyl) -3- (piperazine -1- base) benzsulfamide (145mg, 0.3mmol), sodium cyanoborohydride Crude product is prepared in the reaction in methanol (10mL) of (57mg, 0.9mmol) and formaldehyde (40%, 0.026mL, 0.9mmol), slightly Product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and title compound is obtained after concentrate drying as white Solid (137mg, 92%).
MS(ESI,pos.ion)m/z:498.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 7.85 (d, J=9.0Hz, 1H), 7.71 (d, J=8.0Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=2.0Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.32 (dd, J=8.4,2.1Hz, 1H), 7.26 (t, J=7.8Hz, 1H), 7.23 (d, J=2.1Hz, 1H), 7.15 (dd, J=8.9,2.1Hz, 1H), 7.00 (d, J= 8.4Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 3.14 (d, J=4.2Hz, 2H), 2.84 (brs, 8H), 2.64 (s, 3H), 1.53(s,6H).
19 N- of embodiment (2- (7- fluoronaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulfonyl The synthesis of amine
The synthesis of step 1) 2- (7- fluoronaphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 13 step 1 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene- 1- yl) acetonitrile (1.85g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50.0mmol) and iodomethane Crude product is prepared in (5.0mL, 80.0mmol) reaction in anhydrous DMF (10mL), and crude product is purified by silica gel column chromatography (stone Oily ether/ethyl acetate (v/v)=60/1), it is yellow solid (1.38g, 65%) that title compound is obtained after concentrate drying.
1H NMR(600MHz,CDCl3) δ (ppm): 8.17 (d, J=11.9Hz, 1H), 7.91 (dd, J=8.8,6.2Hz, 1H), 7.84 (d, J=8.1Hz, 1H), 7.54 (d, J=7.2Hz, 1H), 7.42 (t, J=7.8Hz, 1H), 7.34-7.31 (m, 1H),1.97(s,6H).
The synthesis of step 2) 2- (7- fluoronaphthalene -1- base) -2- methylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., in 25 DEG C, by 2- (7- Fluoronaphthalene -1- base) -2- methyl propionitrile (1.06g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reaction in THF (25mL) Crude product is prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), after concentrate drying It is colorless oil (651mg, 60%) to title compound.
MS(ESI,pos.ion)m/z:218.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.37 (dd, J=9.5,5.5Hz, 1H), 7.70-7.63 (m, 2H), 7.48 (dd, J=9.7,2.6Hz, 1H), 7.44-7.41 (m, 2H), 3.25 (s, 2H), 1.58 (s, 6H)
Step 3) N- (2- (7- fluoronaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene -1- Base) -2- methylpropane -1- amine (217mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) The reaction in methylene chloride (6mL) of benzene -1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) is prepared into To crude product, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtains title after concentrate drying Compound is faint yellow solid (364mg, 59%).
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.02 (dd, J=9.0,6.7Hz, 1H), 7.95 (dd, J=13.3, 2.0Hz, 1H), 7.84 (t, J=8.0Hz, 1H), 7.52 (d, J=7.4Hz, 1H), 7.48 (t, J=6.8Hz, 1H), 7.42 (t, J=5.5Hz, 1H), 7.40-7.37 (m, 1H), 7.36 (d, J=2.1Hz, 1H), 7.25 (d, J=2.1Hz, 1H), 7.05 (d, J =8.6Hz, 1H), 3.87 (brs, 7H), 3.15 (d, J=6.8Hz, 2H), 3.03 (brs, 4H), 1.49 (s, 6H)
Step 4) N- (2- (7- fluoronaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide Synthesis
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- (2- (7- fluorine Naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (308mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) are anti-in tetrahydrofuran (20mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying Obtaining title compound is white solid (201mg, 85%).
MS(ESI,pos.ion)m/z:472.0[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.02 (dd, J=9.0,6.7Hz, 1H), 7.97 (dd, J=13.3, 1.9Hz, 1H), 7.85 (d, J=8.1Hz, 1H), 7.51 (d, J=7.3Hz, 2H), 7.41 (t, J=9.5Hz, 2H), 7.32 (dd, J=8.4,2.0Hz, 1H), 7.22 (d, J=2.1Hz, 1H), 7.00 (d, J=8.6Hz, 1H), 3.81 (s, 3H), 3.14 (d, J=5.1Hz, 2H), 2.84 (brs, 4H), 2.83 (brs, 4H), 1.49 (s, 6H)；
13C NMR(150MHz,DMSO-d6) δ (ppm): 159.5 (d, J=240.0Hz), 155.2,142.2,142.0 (d, ), J=6.0Hz 132.8 (d, J=9.0Hz), 132.7,132.2,131.9 (d, J=9.0Hz), 128.4,126.5,125.1, (121.7,116.3,115.4 d, J=25.5Hz), 111.7,110.1 (d, J=22.5Hz), 56.2,52.0,51.4,45.9, 27.7.
20 N- of embodiment (2- (7- fluoronaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) The synthesis of benzsulfamide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- (2- (7- fluoronaphthalene -1- Base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (142mg, 0.3mmol), sodium cyanoborohydride Crude product is prepared in the reaction in methanol (10mL) of (57mg, 0.9mmol) and formaldehyde (40%, 0.026mL, 0.9mmol), slightly Product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and title compound is obtained after concentrate drying as white Solid (133mg, 91%).
MS(ESI,pos.ion)m/z:486.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.02 (dd, J=9.0,6.6Hz, 1H), 7.97 (dd, J=13.3, 2.0Hz, 1H), 7.84 (d, J=8.0Hz, 1H), 7.51 (d, J=7.5Hz, 2H), 7.41 (t, J=7.7Hz, 2H), 7.32 (dd, J=8.5,2.2Hz, 1H), 7.22 (d, J=2.2Hz, 1H), 7.00 (d, J=8.6Hz, 1H), 3.81 (s, 3H), 3.13 (s,2H),2.92(brs,4H),2.42(brs,4H),2.20(s,3H),1.49(s,6H)；
13C NMR(150MHz,DMSO-d6) δ (ppm): 159.3 (d, J=240.6Hz), 155.1,142.0 (d, J= 5.5Hz), 141.7,132.8 (d, J=9.4Hz), 132.7,132.2,131.9 (d, J=8.4Hz), 128.4,126.5, (125.1,121.8,116.3,115.4 d, J=24.8Hz), 111.7,110.1 (d, J=22.4Hz), 56.2,55.1,52.0, 50.1,46.3,27.7.
21 N- of embodiment (2- (7- bromonaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulfonyl The synthesis of amine
The synthesis of step 1) 2- (7- bromonaphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 13 step 1 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene- 1- yl) acetonitrile (2.5g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50.0mmol) and iodomethane Crude product is prepared in (5.0mL, 80.0mmol) reaction in anhydrous DMF (10mL), and crude product is purified by silica gel column chromatography (stone Oily ether/ethyl acetate (v/v)=60/1), it is yellow solid (1.64g, 60%) that title compound is obtained after concentrate drying.
1H NMR(600MHz,CDCl3) δ (ppm): 8.69 (s, 1H), 7.81 (d, J=8.1Hz, 1H), 7.78 (d, J= 8.7Hz, 1H), 7.62 (d, J=8.7Hz, 1H), 7.53 (d, J=7.4Hz, 1H), 7.46 (t, J=7.8Hz, 1H), 1.97 (s, 6H).
The synthesis of step 2) 2- (7- bromonaphthalene -1- base) -2- methylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 2- (7- bromonaphthalene -1- base) -2- methyl propionitrile (1.37g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is in THF (25mL) Crude product is prepared in reaction, and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), is concentrated and dried After obtain title compound be colorless oil (778mg, 56%).
MS(ESI,pos.ion)m/z:278.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.52 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.70 (d, J= 6.8Hz, 1H), 7.54 (d, J=8.7Hz, 1H), 7.51-7.50 (m, 1H), 7.41-7.39 (m, 1H), 3.27 (s, 2H), 1.67 (s,6H).
Step 3) N- (2- (7- bromonaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene -1- Base) -2- methylpropane -1- amine (278mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) The reaction in methylene chloride (6mL) of benzene -1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) is prepared into To crude product, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtains title after concentrate drying Compound is faint yellow solid (366mg, 54%).
MS(ESI,pos.ion)m/z:675.8[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.48 (s, 1H), 7.91 (d, J=8.8Hz, 1H), 7.83 (d, J= 7.9Hz, 1H), 7.62-7.50 (m, 3H), 7.47 (t, J=7.7Hz, 1H), 7.40 (dd, J=8.5,1.9Hz, 1H), 7.26 (d, J=1.8Hz, 1H), 7.05 (d, J=8.6Hz, 1H), 4.00-3.74 (m, 7H), 3.11 (d, J=6.7Hz, 2H), 3.04 (brs,4H),1.49(s,6H).
Step 4) N- (2- (7- bromonaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide Synthesis
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- (2- (7- bromine Naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (339mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) are anti-in tetrahydrofuran (20mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying Obtaining title compound is white solid (261mg, 98%).
MS(ESI,pos.ion)m/z:532.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.49 (s, 1H), 7.90 (d, J=8.7Hz, 1H), 7.82 (d, J= 8.0Hz, 1H), 7.64-7.55 (m, 2H), 7.52 (d, J=7.3Hz, 1H), 7.46 (t, J=7.7Hz, 1H), 7.36 (dd, J= 8.5,1.9Hz, 1H), 7.22 (d, J=1.9Hz, 1H), 6.99 (d, J=8.6Hz, 1H), 3.80 (s, 3H), 3.12 (s, 2H), 2.86 (t, J=3.8Hz, 4H), 2.82 (t, J=3.7Hz, 4H), 1.49 (s, 6H)；
13C NMR(150MHz,DMSO-d6)δ(ppm):155.2,142.3,141.8,133.6,132.8,132.3, 128.5,128.4,128.3,126.7,126.4,121.8,119.2,116.3,111.6,56.2,52.2,51.4,45.9, 40.4,27.8.
22 N- of embodiment (2- (7- bromonaphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) The synthesis of benzsulfamide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- (2- (7- bromonaphthalene -1- Base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (160mg, 0.3mmol), sodium cyanoborohydride Crude product is prepared in the reaction in methanol (10mL) of (57mg, 0.9mmol) and formaldehyde (40%, 0.026mL, 0.9mmol), slightly Product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and title compound is obtained after concentrate drying as white Solid (144mg, 88%).
MS(ESI,pos.ion)m/z:546.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.49 (s, 1H), 7.91 (d, J=8.8Hz, 1H), 7.83 (d, J= 8.0Hz, 1H), 7.62 (dd, J=8.7,1.6Hz, 2H), 7.53 (d, J=6.9Hz, 1H), 7.47 (t, J=7.7Hz, 1H), 7.35 (dd, J=8.5,2.2Hz, 1H), 7.22 (d, J=2.2Hz, 1H), 7.00 (d, J=8.6Hz, 1H), 3.81 (s, 3H), 3.11(s,2H),2.93(brs,4H),2.43(brs,4H),2.20(s,3H),1.49(s,6H)；
13C NMR(150MHz,DMSO-d6)δ(ppm):155.1,141.7,133.6,132.7,132.3,128.4, 128.3,128.3,126.6,126.4,121.8,119.2,116.2,111.6,110.0,56.2,55.2,52.2,50.2, 46.3,40.3,27.8.
23 4- methoxyl group-N- of embodiment ((1- (naphthalene -1- base) cyclopropyl) methyl) -3- (piperazine -1- base) benzsulfamide Synthesis
The synthesis of step 1) 1- (naphthalene -1- base) cyclopropanecarbonitrile
At -30 DEG C, by 2- (naphthalene -1- base) acetonitrile (1.67g, 10.0mmol) and sodium hydride, (60% is dispersed in mineral oil In, 1.2g, 30.0mmol) it is added in anhydrous DMF (10mL), after being stirred to react 1h, it is slowly added dropwise into reaction solution into 1,2- Bromofume (1.75mL, 20.0mmol are dissolved in 10mL DMF) is then to slowly warm up to react 30 minutes at 25 DEG C.Reaction knot Saturated salt solution (30mL) quenching reaction is added into reaction mixture, and is extracted with ethyl acetate (30mL x 3) by Shu Hou.It closes And organic phase, it is dried, filtered with anhydrous sodium sulfate, filtrate decompression is spin-dried for obtaining crude product.Crude by column chromatography purifies (petroleum Ether/ethyl acetate (v/v)=50/1) after obtain title compound be white solid (1.16g, 60%).
MS(ESI,pos.ion)m/z:194.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.40 (d, J=8.4Hz, 1H), 7.91 (d, J=8.4Hz, 1H), 7.86 (d, J=8.4Hz, 1H), 7.66 (t, J=7.2Hz, 1H), 7.57 (t, J=7.2Hz, 1H), 7.49 (d, J=7.2Hz, 1H), 7.43 (t, J=7.2Hz, 1H), 1.86 (q, J=4.8Hz, 2H), 1.45 (q, J=4.8Hz, 2H)
The synthesis of step 2) (1- (naphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 1- (naphthalene -1- base) cyclopropanecarbonitrile (965mg, 5.0mmol) and LiAlH4(950mg, 25.0mmol) reaction system in THF (25mL) Standby to obtain crude product, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), obtains after concentrate drying Title compound is colorless oil (857mg, 87%).
MS(ESI,pos.ion)m/z:198.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.35 (d, J=7.8Hz, 1H), 7.87 (d, J=7.8Hz, 1H), 7.75 (t, J=7.8Hz, 1H), 7.54 (t, J=7.8Hz, 1H), 7.49 (t, J=7.8Hz, 1H), 7.46 (d, J=6.6Hz, 1H), 7.40 (t, J=7.8Hz, 1H), 2.88 (s, br, 2H), 0.98-0.97 (m, 4H)
Step 3) 4- methoxyl group-N- ((1- (naphthalene -1- base) cyclopropyl) methyl) -3- (4- (2,2,2- trichloroacetyl) piperazine Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (1- (naphthalene -1- base) Cyclopropyl) methylamine (197mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulphur Thick production is prepared in the reaction in methylene chloride (6mL) of acyl chlorides (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) Object, crude product are purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtain title compound after concentrate drying For faint yellow solid (488mg, 81.8%).
MS(ESI,pos.ion)m/z:595.8[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.18-8.15 (m, 1H), 7.84-7.83 (m, 1H), 7.74 (d, J= 7.8Hz, 1H), 7.46 (dd, J=6.0,3.6Hz, 2H), 7.41 (d, J=6.6Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 7.22 (d, J=9.0Hz, 1H), 7.12 (s, 1H), 6.66 (d, J=8.4Hz, 1H), 4.33 (s, 2H), 4.11-3.88 (m, 7H),3.00(brs,4H),0.97(s,2H),0.89-0.87(m,2H).
The conjunction of step 4) 4- methoxyl group-N- ((1- (naphthalene -1- base) cyclopropyl) methyl) -3- (piperazine -1- base) benzsulfamide At
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 4- methoxyl group-N- ((1- (naphthalene -1- base) cyclopropyl) methyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (299mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (220mg, 97.2%).
MS(ESI,pos.ion)m/z:452.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.20-8.17 (m, 1H), 7.83-7.81 (m, 1H), 7.73 (d, J= 8.0Hz, 1H), 7.47-7.45 (m, 2H), 7.41-7.34 (m, 2H), 7.17 (dd, J=8.4,2.0Hz, 1H), 7.12 (d, J= 2.0Hz, 1H), 6.63 (d, J=8.4Hz, 1H), 3.85 (s, 3H), 3.10-3.04 (m, 4H), 2.99-2.98 (m, 4H), 2.62 (s,2H),1.05(brs,2H),0.95(brs,2H)；
13C NMR(100MHz,CDCl3)δ(ppm):155.2,141.4,137.3,134.0,132.1,131.7,128.8, 128.5,128.1,126.0,125.7,125.3,124.2,122.5,116.8,110.6,,55.7,51.5,50.6,45.5, 24.1,12.1.
Embodiment 24 4- methoxyl group -3- (4- methylpiperazine-1-yl)-N- ((1- (naphthalene -1- base) cyclopropyl) methyl) benzene sulphur The synthesis of amide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by 4- methoxyl group-N- ((1- (naphthalene -1- base) cyclopropyl) methyl) -3- (piperazine -1- base) benzsulfamide (135mg, 0.3mmol), sodium cyanoborohydride (57mg, 0.9mmol) and crude product, crude product warp is prepared in formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL) Silica gel column chromatography purifies (methylene chloride/methanol (v/v)=30/1), and it is white solid that title compound is obtained after concentrate drying (136mg, 97.6%).
MS(ESI,pos.ion)m/z:466.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.19-8.17 (m, 1H), 7.82-7.81 (m, 1H), 7.72 (d, J= 8.4Hz, 1H), 7.47-7.43 (m, 2H), 7.38-7.37 (m, 1H), 7.36-7.34 (m, 1H), 7.17 (dd, J=8.4, 2.4Hz, 1H), 7.14 (d, J=1.8Hz, 1H), 6.63 (d, J=8.4Hz, 1H), 3.85 (s, 3H), 2.99 (brs, 4H), 2.58 (brs, 6H), 2.34 (s, 3H), 0.96-0.92 (m, 2H), 0.88 (t, J=6.6Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.2,141.3,137.3,134.0,132.1,131.6,128.8, 128.6,128.1,126.1,125.7,125.4,124.2,122.2,116.6,110.5,55.7,55.0,50.1,46.0, 24.2,12.2.
25 N- of embodiment ((1- (6- fluoronaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulfonyl The synthesis of amine
The synthesis of step 1) 1- (6- fluoronaphthalene -1- base) cyclopropanecarbonitrile
This step title compound method referring to described in 23 step 1 of embodiment is prepared, i.e., by 2- (6- fluoronaphthalene- 1- yl) acetonitrile (1.85g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 1.2g, 30.0mmol) and 1,2- dibromo Crude product is prepared in reaction to ethane (1.75mL, 20.0mmol are dissolved in 10mL DMF) in (10mL) in anhydrous DMF, thick to produce Object is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), and it is grayish green that title compound is obtained after concentrate drying Color color solid (1.6g, 76%).
MS(ESI,pos.ion)m/z:212.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.35 (dd, J=9.1,5.6Hz, 1H), 7.72-7.69 (m, 1H), 7.45 (dd, J=9.1,2.4Hz, 1H), 7.43-7.41 (m, 2H), 7.29 (td, J=8.8,2.8Hz, 1H), 0.99 (brs, 2H),0.94(brs,2H).
The synthesis of step 2) (1- (6- fluoronaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 1- (6- fluoronaphthalene -1- base) cyclopropanecarbonitrile (1.05g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is anti-in THF (25mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), after concentrate drying Obtaining title compound is colorless oil (957mg, 89%).
MS(ESI,pos.ion)m/z:216.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.37 (dd, J=9.3,5.6Hz, 1H), 7.70-7.68 (m, 1H), 7.47 (dd, J=9.6,2.4Hz, 1H), 7.43-7.41 (m, 2H), 7.31 (td, J=8.8,2.8Hz, 1H), 2.87 (s, 2H), 0.97(brs,2H),0.93(brs,2H).
Step 3) N- ((1- (6- fluoronaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- (2,2,2- tribromo-acetyl Base) piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (1- (6- fluoronaphthalene- 1- yl) cyclopropyl) methylamine (215mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene - The reaction in methylene chloride (6mL) of 1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) is prepared thick Product, crude product are purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtain title compound after concentrate drying Object is white solid (588mg, 95.6%).
1H NMR(400MHz,CDCl3) δ (ppm): 8.17 (dd, J=9.2,5.6Hz, 1H), 7.66 (d, J=7.6Hz, 1H), 7.43 (dd, J=9.6,5.6Hz, 1H), 7.39-7.34 (m, 2H), 7.22 (td, J=8.8,2.8Hz, 1H), 7.17 (dd, J=8.4,2.0Hz, 1H), 7.04 (d, J=1.6Hz, 1H), 6.64 (d, J=8.8Hz, 1H), 4.38 (t, J=9.0Hz, 1H), 3.94 (brs, 4H), 3.88 (s, 3H), 3.16 (s, 2H), 2.89 (t, J=4.8Hz, 4H), 0.96 (brs, 2H), 0.89- 0.83(m,2H).
Step 4) N- ((1- (6- fluoronaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide Synthesis
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- ((1- (6- fluorine Naphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (307mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) are anti-in tetrahydrofuran (20mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying Obtaining title compound is white solid (202mg, 86.2%).
MS(ESI,pos.ion)m/z:470.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.18 (dd, J=9.6,6.0Hz, 1H), 7.66 (d, J=7.8Hz, 1H), 7.42 (dd, J=9.6,2.4Hz, 1H), 7.38-7.34 (m, 2H), 7.23 (td, J=8.4,2.4Hz, 1H), 7.15 (dd, J=8.4,1.8Hz, 1H), 7.10 (d, J=1.8Hz, 1H), 6.63 (d, J=8.4Hz, 1H), 3.86 (s, 3H), 3.16- 2.96(m,6H),2.90(brs,4H),0.94(brs,2H),0.88-0.85(m,2H)；
13C NMR(150MHz,CDCl3) δ (ppm): 160.4 (d, J=244.95Hz), 155.3,141.8,137.6, 134.9 (d, J=8.85Hz), 131.4,129.1,127.8 (d, J=2.1Hz), 127.4 (d, J=5.1Hz), 126.8 (d, J =8.7Hz), 126.5,122.2,116.6,116.2 (d, J=24.75Hz), 111.7 (d, J=19.8Hz), 110.4,55.7, 51.5,45.9,24.2,12.0.
26 N- of embodiment ((1- (6- fluoronaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) The synthesis of benzsulfamide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- ((1- (6- fluoronaphthalene -1- Base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (141mg, 0.3mmol), sodium cyanoborohydride Crude product is prepared in the reaction in methanol (10mL) of (57mg, 0.9mmol) and formaldehyde (40%, 0.026mL, 0.9mmol), slightly Product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and title compound is obtained after concentrate drying as white Solid (87mg, 60.2%).
MS(ESI,pos.ion)m/z:484.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.17 (dd, J=9.2,5.6Hz, 1H), 7.62 (dd, J=6.4, 3.2Hz, 1H), 7.39 (dd, J=9.6,2.0Hz, 1H), 7.34-7.31 (m, 2H), 7.20 (td, J=9.2,1.6Hz, 1H), 7.15 (d, J=8.4Hz, 1H), 7.13 (s, 1H), 6.62 (d, J=8.4Hz, 1H), 3.84 (s, 3H), 3.20 (s, 2H), 2.96 (brs,4H),2.55(brs,4H),2.31(s,3H),1.02(brs,2H),0.90(brs,2H)；
13C NMR(100MHz,CDCl3) δ (ppm): 160.4 (d, J=244.9Hz), 155.2,141.4,137.8, 134.9 (d, J=8.9Hz), 131.6,129.1,127.8 (d, J=2.2Hz), 127.3 (d, J=5.1Hz), 126.8 (d, J= 8.3Hz), 126.5,122.1,116.5,116.2 (d, J=24.7Hz), 111.6 (d, J=19.8Hz), 110.5,55.7, 55.0,51.5,50.0,45.9,24.2,12.0.
27 4- methoxyl group-N- of embodiment ((1- (7- methoxynaphthalene -1- base) cyclopropyl) methyl) -3- (piperazine -1- base) benzene The synthesis of sulfonamide
The synthesis of step 1) 1- (7- methoxynaphthalene -1- base) cyclopropanecarbonitrile
This step title compound method referring to described in 23 step 1 of embodiment is prepared, i.e., by 2- (7- methoxyl group Naphthalene -1- base) acetonitrile (1.97g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 1.2g, 30.0mmol) and 1,2- bis- Crude product is prepared in bromoethane (1.75mL, 20.0mmol are dissolved in 10mL DMF) reaction in anhydrous DMF (10mL), thick to produce Object is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), and it is grayish green that title compound is obtained after concentrate drying Color color solid (1.45g, 65%).
MS(ESI,pos.ion)m/z:224.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.81 (d, J=9.0Hz, 1H), 7.78 (d, J=7.8Hz, 1H), 7.61 (d, J=1.8Hz, 1H), 7.46 (d, J=6.6Hz, 1H), 7.29 (t, J=7.2Hz, 1H), 7.23 (dd, J=9.0, 2.4Hz, 1H), 4.02 (s, 3H), 1.85 (q, J=4.8Hz, 2H), 1.44 (q, J=4.8Hz, 2H)
The synthesis of step 2) (1- (7- methoxynaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 1- (7- methoxynaphthalene -1- base) cyclopropanecarbonitrile (1.12g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is at THF (25mL) Crude product is prepared in middle reaction, and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), and concentration is dry It is colorless oil (817mg, 72%) that title compound is obtained after dry.
MS(ESI,pos.ion)m/z:228.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.76 (d, J=9.0Hz, 1H), 7.67 (d, J=7.8Hz, 1H), 7.62 (d, J=2.4Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.26 (t, J=8.4Hz, 1H), 7.17 (dd, J=9.0, 2.4Hz,1H),3.95(s,3H),2.87(s,2H),0.95(brs,4H).
Step 3) 4- methoxyl group-N- ((1- (7- methoxynaphthalene -1- base) cyclopropyl) methyl) -3- (4- (tri- chloroethene of 2,2,2- Acyl group) piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (1- (7- methoxyl group Naphthalene -1- base) cyclopropyl) methylamine (227mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) The reaction in methylene chloride (6mL) of benzene -1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) is prepared into To crude product, crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtains title after concentrate drying Compound is faint yellow solid (558mg, 89.0%).
MS(ESI,pos.ion)m/z:625.8[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.73 (d, J=9.0Hz, 1H), 7.66 (d, J=8.1Hz, 1H), 7.48 (d, J=1.8Hz, 1H), 7.37 (d, J=6.6Hz, 1H), 7.24-7.21 (m, 2H), 7.14 (dd, J=9.0,2.4Hz, 1H), 7.10 (s, 1H), 6.68 (d, J=8.4Hz, 1H), 4.37 (t, J=5.4Hz, NH), 4.01-3.91 (m, 7H), 3.89 (s,3H),3.13-2.85(m,6H),0.97-0.87(m,4H).
Step 4) 4- methoxyl group-N- ((1- (7- methoxynaphthalene -1- base) cyclopropyl) methyl) -3- (piperazine -1- base) benzene sulphur The synthesis of amide
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 4- methoxyl group-N- ((1- (7- methoxynaphthalene -1- base) cyclopropyl) methyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (313mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) are anti-in tetrahydrofuran (20mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying Obtaining title compound is white solid (238mg, 98.6%).
MS(ESI,pos.ion)m/z:482.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.73 (d, J=8.8Hz, 1H), 7.66 (d, J=8.0Hz, 1H), 7.51 (d, J=2.4Hz, 1H), 7.37 (dd, J=7.2,1.2Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.20 (dd, J= 8.4,2.4Hz, 1H), 7.13 (td, J=4.4,2.8Hz, 2H), 6.66 (d, J=8.4Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H),3.10-3.07(m,4H),2.99-2.96(m,4H),2.69(s,2H),0.97-0.96(m,2H),0.90-0.85(m, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):157.7,155.3,141.5,135.9,133.4,131.7,130.3, 129.4,129.0,127.7,123.1,122.4,118.1,116.7,110.6,103.1,55.7,55.4,50.9,50.7, 45.6,24.2,12.1.
28 4- methoxyl group-N- of embodiment ((1- (7- methoxynaphthalene -1- base) cyclopropyl) methyl) -3- (4- methyl piperazine - 1- yl) benzsulfamide synthesis
This step title compound method referring to described in embodiment 2 is prepared, i.e., by 4- methoxyl group-N- ((1- (7- methoxynaphthalene -1- base) cyclopropyl) methyl) -3- (piperazine -1- base) benzsulfamide (145mg, 0.3mmol), cyano hydroboration Crude product is prepared in the reaction in methanol (10mL) of sodium (57mg, 0.9mmol) and formaldehyde (40%, 0.026mL, 0.9mmol), Crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and it is white that title compound is obtained after concentrate drying Color solid (143mg, 96.0%).
MS(ESI,pos.ion)m/z:496.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.71 (d, J=9.0Hz, 1H), 7.64 (d, J=7.8Hz, 1H), 7.51 (d, J=2.4Hz, 1H), 7.35-7.34 (m, 1H), 7.22-7.19 (m, 2H), 7.15 (d, J=2.4Hz, 1H), 7.12 (dd, J=9.0,2.4Hz, 1H), 6.65 (d, J=8.4Hz, 1H), 4.68 (s, NH), 3.91 (s, 3H), 3.85 (s, 3H), 3.16 (brs, 2H), 2.98 (brs, 4H), 2.57 (brs, 4H), 2.33 (s, 3H), 0.93 (brs, 2H), 0.88 (t, J= 6.6Hz,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.7,155.2,141.4,136.0,133.4,131.7,130.3, 129.3,129.0,127.7,123.1,122.2,118.1,116.5,110.5,103.0,55.8,55.4,55.0,50.1, 46.0,24.2,11.9.
29 N- of embodiment ((1- (7- fluoronaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulfonyl The synthesis of amine
The synthesis of step 1) 1- (7- fluoronaphthalene -1- base) cyclopropanecarbonitrile
This step title compound method referring to described in 23 step 1 of embodiment is prepared, i.e., by 2- (7- fluoronaphthalene- 1- yl) acetonitrile (1.85g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 1.2g, 30.0mmol) and 1,2- dibromo Crude product, crude product is prepared in ethane (1.75mL, 20.0mmol are dissolved in 10mL DMF) reaction in anhydrous DMF (10mL) It is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), it is celadon that title compound is obtained after concentrate drying Color solid (1.33g, 63%).
MS(ESI,pos.ion)m/z:212.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.98 (d, J=10.6Hz, 1H), 7.90 (dd, J=8.9,5.8Hz, 1H), 7.85 (d, J=8.3Hz, 1H), 7.53 (d, J=7.1Hz, 1H), 7.41 (d, J=7.8Hz, 1H), 7.38-7.32 (m, 1H), 1.87 (q, J=4.9Hz, 2H), 1.43 (q, J=4.9Hz, 2H)
The synthesis of step 2) (1- (7- fluoronaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 1- (7- fluoronaphthalene -1- base) cyclopropanecarbonitrile (1.05g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is anti-in THF (25mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), after concentrate drying Obtaining title compound is colorless oil (623mg, 58%).
MS(ESI,pos.ion)m/z:216.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.96 (dd, J=11.3,2.3Hz, 1H), 7.87 (dd, J=8.9, 5.9Hz, 1H), 7.76 (d, J=8.2Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 7.28 (td, J=8.9,2.5Hz, 1H), 2.35 (s, 2H), 0.99-0.94 (m, 4H)
Step 3) N- ((1- (7- fluoronaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- (2,2,2- tribromo-acetyl Base) piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (1- (7- fluoronaphthalene- 1- yl) cyclopropyl) methylamine (215mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene - The reaction in methylene chloride (6mL) of 1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) is prepared thick Product, crude product are purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtain title compound after concentrate drying Object is faint yellow solid (443mg, 72%).
MS(ESI,pos.ion)m/z:614.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.00 (dd, J=9.0,6.1Hz, 1H), 7.90 (dd, J=11.5, 2.2Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.54-7.49 (m, 2H), 7.43-7.38 (m, 2H), 7.24 (dd, J=8.5, 2.0Hz, 1H), 7.12 (d, J=2.0Hz, 1H), 6.95 (d, J=8.6Hz, 1H), 3.92-3.68 (m, 7H), 3.16-2.82 (m,6H),1.10-1.02(m,2H),0.76(brs,2H).
Step 4) N- ((1- (7- fluoronaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide Synthesis
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- ((1- (7- fluorine Naphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (308mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) are anti-in tetrahydrofuran (20mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying Obtaining title compound is white solid (234mg, 99.7%).
MS(ESI,pos.ion)m/z:470.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.01 (dd, J=8.9,6.1Hz, 1H), 7.92 (dd, J=11.5, 2.0Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.53 (s, 1H), 7.50 (d, J=7.0Hz, 1H), 7.44-7.37 (m, 2H), 7.20 (dd, J=8.5,1.8Hz, 1H), 7.11 (d, J=1.9Hz, 1H), 6.91 (d, J=8.5Hz, 1H), 3.80 (s, 3H), 3.16(s,2H),2.86-2.82(m,8H),1.03(brs,2H),0.76(brs,2H)；
13C NMR(150MHz,DMSO-d6) δ (ppm): 160.4 (d, J=241.6Hz), 155.1,142.2,138.6 (d, ), J=5.6Hz 133.3 (d, J=8.8Hz), 132.5,132.1 (d, J=9.1Hz), 131.1,130.1,127.9,125.3, (121.7,116.2,116.0,111.6,108.2 d, J=21.0Hz), 56.2,51.5,50.5,46.0,24.1,11.4.
30 N- of embodiment ((1- (7- fluoronaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) The synthesis of benzsulfamide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- ((1- (7- fluoronaphthalene -1- Base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (141mg, 0.3mmol), sodium cyanoborohydride Crude product is prepared in the reaction in methanol (10mL) of (57mg, 0.9mmol) and formaldehyde (40%, 0.026mL, 0.9mmol), slightly Product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and title compound is obtained after concentrate drying as white Solid (123mg, 85%).
MS(ESI,pos.ion)m/z:484.2[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.01 (dd, J=9.0,6.1Hz, 1H), 7.91 (dd, J=11.5, 2.4Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.52 (t, J=6.4Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.43- 7.38 (m, 2H), 7.19 (dd, J=8.5,2.2Hz, 1H), 7.11 (d, J=2.2Hz, 1H), 6.91 (d, J=8.6Hz, 1H), 3.80(s,3H),3.17(s,2H),2.90(brs,4H),2.44(brs,4H),2.21(s,3H),1.05-1.01(m,2H), 0.79-0.67(m,2H)；
13C NMR(150MHz,DMSO-d6) δ (ppm): 161.4 (d, J=243.0Hz), 155.0,141.6,138.6 (d, ), J=6.0Hz 133.3 (d, J=9.0Hz), 132.5,132.1 (d, J=9.0Hz), 131.1,130.1,127.8,125.2, (121.7,116.1,116.0,111.6,108.2 d, J=21.0Hz), 56.2,55.1,50.5,50.1,46.2,24.1.
31 N- of embodiment ((1- (7- bromonaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulfonyl The synthesis of amine
The synthesis of step 1) 1- (7- bromonaphthalene -1- base) cyclopropanecarbonitrile
This step title compound method referring to described in 23 step 1 of embodiment is prepared, i.e., by 2- (7- bromonaphthalene- 1- yl) acetonitrile (2.46g, 10.0mmol), sodium hydride (60% is dispersed in mineral oil, 1.2g, 30.0mmol) and 1,2- dibromo Crude product is prepared in reaction to ethane (1.75mL, 20.0mmol are dissolved in 10mL DMF) in (10mL) in anhydrous DMF, thick to produce Object is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), and it is grayish green that title compound is obtained after concentrate drying Color color solid (1.58g, 58%).
1H NMR(600MHz,CDCl3) δ (ppm): 8.52 (s, 1H), 7.82 (d, J=8.2Hz, 1H), 7.77 (d, J= 8.7Hz, 1H), 7.64 (dd, J=8.7,1.7Hz, 1H), 7.52 (d, J=7.1Hz, 1H), 7.45-7.43 (m, 1H), 1.88 (q, J=4.9Hz, 2H), 1.43 (q, J=4.9Hz, 2H)
The synthesis of step 2) (1- (7- bromonaphthalene -1- base) cyclopropyl) methylamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., at 25 DEG C, by 1- (7- bromonaphthalene -1- base) cyclopropanecarbonitrile (1.36g, 5.0mmol) and LiAlH4(950mg, 25.0mmol) is anti-in THF (25mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), after concentrate drying Obtaining title compound is colorless oil (1.17g, 85%).
MS(ESI,pos.ion)m/z:276.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.46-8.37 (m, 1H), 7.90-7.84 (m, 1H), 7.74 (t, J= 8.4Hz, 1H), 7.47 (dd, J=6.4,3.1Hz, 1H), 7.42-7.38 (m, 2H), 2.86 (s, br, 2H), 0.96 (brs, 4H).
Step 3) N- ((1- (7- bromonaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- (2,2,2- tribromo-acetyl Base) piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (1- (7- bromonaphthalene- 1- yl) cyclopropyl) methylamine (276mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene - The reaction in methylene chloride (6mL) of 1- sulfonic acid chloride (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) is prepared thick Product, crude product are purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtain title compound after concentrate drying Object is faint yellow solid (466mg, 69%).
MS(ESI,pos.ion)m/z:674.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.40 (d, J=1.3Hz, 1H), 7.89 (d, J=8.8Hz, 1H), 7.82 (d, J=7.8Hz, 1H), 7.61 (dd, J=8.7,1.8Hz, 1H), 7.55 (t, J=6.3Hz, 1H), 7.52-7.49 (m, 1H), 7.48-7.44 (m, 1H), 7.24 (dd, J=8.5,2.0Hz, 1H), 7.11 (d, J=2.1Hz, 1H), 6.95 (d, J= 8.6Hz,1H),3.99-3.73(m,7H),3.14-2.81(m,6H),1.13-0.96(m,2H),0.77(brs,2H).
Step 4) N- ((1- (7- bromonaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide Synthesis
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- ((1- (7- bromine Naphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (338mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) are anti-in tetrahydrofuran (20mL) Crude product should be prepared, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying Obtaining title compound is white solid (156mg, 59%).
MS(ESI,pos.ion)m/z:530.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.41 (s, 1H), 7.89 (d, J=8.7Hz, 1H), 7.82 (d, J= 8.0Hz, 1H), 7.62 (dd, J=8.7,1.8Hz, 1H), 7.57 (s, 1H), 7.53-7.48 (m, 1H), 7.46 (t, J= 7.6Hz, 1H), 7.21 (dd, J=8.5,2.1Hz, 1H), 7.11 (d, J=2.1Hz, 1H), 6.92 (d, J=8.6Hz, 1H), 3.81(s,3H),3.02-2.74(m,10H),1.1-1.0(m,2H),0.84-0.76(m,2H)；
13C NMR(150MHz,DMSO-d6)δ(ppm):155.1,142.0,138.3,133.5,132.6,132.5, 131.5,130.3,129.0,127.9,126.7,126.5,121.8,120.0,116.2,111.6,56.2,51.1,50.5, 45.7,24.1.
32 N- of embodiment ((1- (7- bromonaphthalene -1- base) cyclopropyl) methyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) The synthesis of benzsulfamide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- ((1- (7- bromonaphthalene -1- Base) cyclopropyl) methyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (159mg, 0.3mmol), sodium cyanoborohydride Crude product is prepared in the reaction in methanol (10mL) of (57mg, 0.9mmol) and formaldehyde (40%, 0.026mL, 0.9mmol), slightly Product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), and title compound is obtained after concentrate drying as white Solid (135mg, 83%).
MS(ESI,pos.ion)m/z:544.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.29 (s, 1H), 7.66-7.64 (m, 2H), 7.50 (dd, J=8.7, 1.7Hz, 1H), 7.39 (d, J=7.0Hz, 1H), 7.34-7.30 (m, 1H), 7.22 (dd, J=8.5,2.1Hz, 1H), 7.14 (d, J=2.1Hz, 1H), 6.66 (d, J=8.6Hz, 1H), 3.85 (s, 3H), 2.98 (brs, 6H), 2.56 (brs, 4H), 2.31 (s,3H),1.03-0.98(m,2H),0.91-0.88(m,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.1,141.4,136.5,133.2,132.2,131.4,130.4, 129.6,128.9,127.8,126.3,125.7,122.2,120.2,116.4,110.4,55.6,54.9,51.2,50.0, 45.8,23.9.
33 4- methoxyl group-N- of embodiment (2- (4- methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide Synthesis
The synthesis of step 1) (E) -1- methoxyl group -4- (2- nitroethenyl group) naphthalene
By 4- methoxy-1-naphthalene formaldehyde (1.0g, 5.4mmol) and NH4OAc (0.208g, 2.7mmol) is added to nitro first In alkane (10mL), reaction solution reacts 7h under 120 DEG C of oil baths.After reaction, ethyl acetate is added into reaction mixture (60mL) dilution, and washed with saturated salt solution (40mL x 3).After liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, filter Liquid decompression is spin-dried for obtaining crude product.It is yellow solid that title compound is obtained after crude by column chromatography purifying (methylene chloride) (1.1g, 89%).
MS(ESI,pos.ion)m/z:230.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.78 (d, J=13.3Hz, 1H), 8.30-8.17 (m, 4H), 7.72- 7.68 (m, 1H), 7.63-7.59 (m, 1H), 7.11 (d, J=8.3Hz, 1H), 4.07 (s, 3H)
The synthesis of step 2) 2- (4- methoxynaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., will at 25 DEG C (E) -1- methoxyl group -4- (2- nitroethenyl group) naphthalene (1.1g, 4.8mmol) and LiAlH4(950mg, 25.0mmol) is in THF Crude product is prepared in reaction in (25mL), and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), It is brown oil (360mg, 37%) that title compound is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:202.1[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.35-8.33 (m, 1H), 8.00 (d, J=8.5Hz, 1H), 7.58- 7.49 (m, 2H), 7.28-7.25 (m, 1H), 6.77 (d, J=7.8Hz, 1H), 4.01 (s, 3H), 3.16 (t, J=6.5Hz, 2H),3.09-3.06(m,2H).
Step 3) 4- methoxyl group-N- (2- (4- methoxynaphthalene -1- base) ethyl) -3- (4- (2,2,2- trichloroacetyl) piperazine Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (4- methoxyl group Naphthalene -1- base) ethamine (201mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulphur Thick production is prepared in the reaction in methylene chloride (6mL) of acyl chlorides (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol) Object, crude product are purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtain title compound after concentrate drying For faint yellow solid (507mg, 84.4%).
MS(ESI,pos.ion)m/z:600.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.30-8.27(m,1H),7.78-7.75(m,1H),7.51-7.47 (m, 2H), 7.45 (dd, J=8.6,2.2Hz, 1H), 7.20 (d, J=2.2Hz, 1H), 7.16 (d, J=7.8Hz, 1H), 6.82 (d, J=8.6Hz, 1H), 6.70 (d, J=7.8Hz, 1H), 3.98-3.91 (m, 10H), 3.27 (t, J=6.2Hz, 2H), 3.17 (t, J=6.8Hz, 2H), 3.04 (t, J=4.9Hz, 4H)
The conjunction of step 4) 4- methoxyl group-N- (2- (4- methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide At
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 4- methoxyl group-N- (2- (4- methoxynaphthalene -1- base) ethyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (300mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (173mg, 76%).
MS(ESI,pos.ion)m/z:456.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.31-8.27 (m, 1H), 7.81 (dd, J=6.2,2.0Hz, 1H), 7.50-7.42 (m, 3H), 7.33 (d, J=2.2Hz, 1H), 7.16 (d, J=7.8Hz, 1H), 6.81 (d, J=8.6Hz, 1H), 6.70 (d, J=7.8Hz, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.27 (t, J=6.8Hz, 2H), 3.18 (t, J= 6.8Hz,2H),3.11-3.10(m,4H),3.05-3.04(m,4H)；
13C NMR(CDCl3,100MHz)δ(ppm):155.4,154.7,141.7,132.3,131.5,127.0,126.7, 125.9,125.5,125.0,123.1,122.7,122.6,116.8,115.5,110.6,103.2,55.8,55.4,50.7, 45.5,43.5,32.6.
34 4- methoxyl group-N- of embodiment (2- (4- methoxynaphthalene -1- base) ethyl) -3- (4- methylpiperazine-1-yl) benzene sulphur The synthesis of amide
This step title compound method referring to described in embodiment 2 is prepared, i.e., by 4- methoxyl group-N- (2- (4- Methoxynaphthalene -1- base) ethyl) -3- (piperazine -1- base) benzsulfamide (137mg, 0.3mmol), sodium cyanoborohydride (57mg, 0.9mmol) and crude product, crude product warp is prepared in formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL) Silica gel column chromatography purifies (methylene chloride/methanol (v/v)=30/1), and it is white solid that title compound is obtained after concentrate drying (123mg, 87%).
MS(ESI,pos.ion)m/z:470.3[M+H]+；
1H NMR(CDCl3, 400MHz) δ (ppm): 8.28-8.26 (m, 1H), 7.77 (d, J=7.3Hz, 1H), 7.45 (t, J=3.1Hz, 2H), 7.40 (dd, J=8.4,1.7Hz, 1H), 7.29 (d, J=1.7Hz, 1H), 7.13 (d, J=7.8Hz, 1H), 6.79 (d, J=8.6Hz, 1H), 6.68 (d, J=7.8Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.27-3.25 (m, 2H), 3.14 (t, J=6.9Hz, 2H), 2.57 (brs, 4H), 2.33 (brs, 4H), 2.15 (s, 3H)；
13C NMR(CDCl3,100MHz)δ(ppm):155.3,154.7,141.6,132.3,131.6,126.9,126.7, 125.9,125.4,125.0,123.0,122.7,122.4,116.6,110.6,103.2,55.7,55.4,55.0,50.1, 46.0,43.4,32.7.
The synthesis of 35 N- of embodiment (2- (4- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide
The synthesis of step 1) (E) -1- fluoro- 4- (2- nitroethenyl group) naphthalene
This step title compound method referring to described in 33 step 1 of embodiment is prepared, i.e., by the fluoro- 1- naphthalene first of 4- Aldehyde (1.0g, 5.75mmol) and NH4Crude product is prepared in OAc (0.22g, 2.9mmol) reaction in nitromethane (10mL), Crude product is purified by silica gel column chromatography (methylene chloride), obtained after concentrate drying title compound be celadon solid (1.0g, 80%).
MS(ESI,pos.ion)m/z:218.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.76 (d, J=13.3Hz, 1H), 8.34 (d, J=8.2Hz, 1H), 8.21 (d, J=13.3Hz, 1H), 8.14-8.10 (m, 2H), 7.79-7.71 (m, 2H), 7.45 (dd, J=10.4,8.3Hz, 1H).
The synthesis of step 2) 2- (4- fluoronaphthalene -1- base) ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., will at 25 DEG C (E) the fluoro- 4- of -1- (2- nitroethenyl group) naphthalene (1.0g, 4.6mmol) and LiAlH4(950mg, 25.0mmol) is at THF (25mL) Crude product is prepared in middle reaction, and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), and concentration is dry It is brown oil (443mg, 51%) that title compound is obtained after dry.
MS(ESI,pos.ion)m/z:190.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.13-8.11(m,1H),8.10-7.99(m,1H),7.56-7.50 (m, 2H), 7.23 (dd, J=7.8,5.5Hz, 1H), 7.04 (dd, J=10.3,7.8Hz, 1H), 3.18 (t, J=7.0Hz, 2H), 3.06 (t, J=6.9Hz, 2H)
Step 3) N- (2- (4- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- Base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (4- fluoronaphthalene -1- Base) ethamine (189mg, 1.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride Crude product is prepared in the reaction in methylene chloride (6mL) of (523mg, 1.2mmol) and triethylamine (0.5mL, 3.0mmol), slightly Product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), and it is light that title compound is obtained after concentrate drying Yellow solid (395mg, 67%).
MS(ESI,pos.ion)m/z:588.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.12 (dd, J=6.1,3.5Hz, 1H), 7.88 (d, J=6.3Hz, 1H), 7.54 (q, J=3.2Hz, 2H), 7.47 (d, J=8.5Hz, 1H), 7.36 (s, 1H), 7.17 (dd, J=7.6,5.5Hz, 1H), 7.03 (dd, J=10.2,7.8Hz, 1H), 6.86 (d, J=8.6Hz, 1H), 3.93 (brs, 7H), 3.30 (t, J= 6.0Hz, 2H), 3.23 (t, J=6.4Hz, 2H), 3.13 (brs, 4H)
The synthesis of step 4) N- (2- (4- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- (2- (4- fluorine Naphthalene -1- base) ethyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (295mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (20mL) Crude product is obtained, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is marked after concentrate drying Topic compound is white solid (164mg, 74%).
MS(ESI,pos.ion)m/z:444.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.06-8.04 (m, 1H), 7.93 (dd, J=4.4,1.9Hz, 1H), 7.62 (dd, J=6.4,3.2Hz, 3H), 7.36 (dd, J=8.4,1.8Hz, 1H), 7.30 (dd, J=7.7,5.7Hz, 1H), 7.22 (t, J=9.2Hz, 2H), 7.04 (d, J=8.6Hz, 1H), 3.83 (s, 3H), 3.11 (t, J=7.4Hz, 2H), 2.99- 2.98 (m, 2H), 2.87 (brs, 4H), 2.83 (t, J=3.7Hz, 4H)；
13C NMR(100MHz,DMSO-d6) δ (ppm): 157.4 (d, J=247.0Hz), 155.3,142.4,132.9 (d, ), J=4.4Hz 132.5,131.5 (d, J=4.2Hz), 127.7,127.1 (d, J=8.3Hz), 126.8,124.1 (d, J= 2.4Hz), 123.6 (d, J=16.0Hz), 121.9,121.0 (d, J=5.6Hz), 116.3,111.8,109.6 (d, J= 19.2Hz),56.3,51.5,46.0,43.9,32.5.
36 N- of embodiment (2- (4- fluoronaphthalene -1- base) ethyl) -4- methoxyl group -3- (4- methylpiperazine-1-yl) benzsulfamide Synthesis
This step title compound method referring to described in embodiment 2 is prepared, i.e., by N- (2- (4- fluoronaphthalene -1- Base) ethyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide (133mg, 0.3mmol), sodium cyanoborohydride (57mg, 0.9mmol) and crude product, crude product warp is prepared in formaldehyde (40%, 0.026mL, 0.9mmol) reaction in methanol (10mL) Silica gel column chromatography purifies (methylene chloride/methanol (v/v)=30/1), and it is white solid that title compound is obtained after concentrate drying (122mg, 89%).
MS(ESI,pos.ion)m/z:458.3[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.04 (dd, J=6.1,3.3Hz, 1H), 7.94-7.93 (m, 1H), 7.62-7.60 (m, 3H), 7.36 (dd, J=8.5,2.1Hz, 1H), 7.31-7.29 (m, 1H), 7.23-7.21 (m, 2H), 7.04 (d, J=8.6Hz, 1H), 3.83 (s, 3H), 3.11 (t, J=7.4Hz, 2H), 2.99 (t, J=7.4Hz, 2H), 2.95 (brs, 4H),2.44(brs,4H),2.20(s,3H)；
13C NMR(150MHz,DMSO-d6) δ (ppm): 157.5 (d, J=246.9Hz), 155.3,141.8,132.9 (d, ), J=4.2Hz 132.4,131.5 (d, J=4.1Hz), 127.8,127.2 (d, J=8.2Hz), 126.9,124.2,123.6 (d, J=16.1Hz), 122.1,121.1 (d, J=5.3Hz), 116.3,111.8,109.7 (d, J=19.1Hz), 56.3, 55.2,50.2,46.3,43.9,32.6.
The synthesis of 37 N- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The synthesis of step 1) 4- (piperazine -1- base) -1- naphthaldehyde
By 1- naphthaldehyde (17.42g, 100mmol), piperazine (25.84g, 300mmol) and potassium carbonate (27.64g, It 200mmol) is added in DMF (50mL), then reaction solution reacts overnight under 160 DEG C of oil baths.After reaction, mixed to reaction It closes in object and methylene chloride (100mL) is added, and washed with saturated sodium chloride solution (50mL).After liquid separation, the anhydrous sulphur of organic phase Sour sodium dries, filters, and filtrate decompression is spin-dried for obtaining crude product.Crude by column chromatography purifying (methylene chloride/methanol (v/v)= 10/1) it is faint yellow solid (22.6g, 94.2%) that title compound is obtained after.
MS(ESI,pos.ion)m/z:241.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 10.23 (s, 1H), 9.33 (d, J=8.4Hz, 1H), 8.19 (d, J= 8.4Hz, 1H), 7.90 (d, J=7.6Hz, 1H), 7.67-7.64 (m, 1H), 7.57-7.55 (m, 1H), 7.11 (d, J= 7.8Hz,1H),3.19(brs,8H).
The synthesis of step 2) 4- (4- formoxyl naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
By 4- (piperazine -1- base) -1- naphthaldehyde (12.02g, 50mmol) and (Boc)2O (13.1g, 60mmol) is added to In tetrahydrofuran (60mL), then reaction solution reacts overnight under 70 DEG C of oil baths.After reaction, reaction solution is subjected to decompression rotation It is dry, obtain crude product.Title compound is obtained after crude by column chromatography purifying (petrol ether/ethyl acetate (v/v)=10/1) For faint yellow solid (11.6g, 68.5%).
MS(ESI,pos.ion)m/z:341.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 10.24 (s, 1H), 9.33 (d, J=9.0Hz, 1H), 8.19 (d, J= 8.4Hz, 1H), 7.90 (d, J=7.8Hz, 1H), 7.69-7.66 (m, 1H), 7.59-7.57 (m, 1H), 7.12 (d, J= 7.8Hz,1H),3.74(brs,4H),3.18(brs,4H),1.51(s,9H).
The synthesis of step 3) (E) -4- (4- (2- nitroethenyl group) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 33 step 1 of embodiment is prepared, i.e., by 4- (4- formoxyl Naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (5.0g, 14.69mmol) and NH4OAc (1.7g, 22.03mmol) is in nitromethane Crude product is prepared in reaction in (30mL), and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=15/ 1) it is Orange red solid (4.4g, 81.0%) that title compound, is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:384.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.81 (d, J=13.2Hz, 1H), 8.25 (d, J=8.4Hz, 1H), 8.16 (d, J=7.8Hz, 1H), 7.75 (d, J=7.8Hz, 1H), 7.66-7.64 (m, 2H), 7.59 (t, J=7.8Hz, 1H), 7.09 (d, J=7.8Hz, 1H), 3.74-3.72 (m, 4H), 3.15 (brs, 4H), 1.51 (s, 9H)
The synthesis of step 4) 4- (4- (2- nitro-ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
(E) -4- (4- (2- nitroethenyl group) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (4.7g, 12.26mmol) is molten In the in the mixed solvent of methanol (25mL) and tetrahydrofuran (5mL), then at 0 DEG C, it is slowly added in batches in Xiang Shangshu solution Sodium borohydride (1.16g, 30.64mmol).Reaction solution reacts overnight at room temperature, obtains crude product.Crude product is through silica gel column layer Analysis purifying (methylene chloride/methanol (v/v)=100/1), obtained after concentrate drying title compound be yellow solid (4.3g, 91.1%).
MS(ESI,pos.ion)m/z:386.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.30 (d, J=8.4Hz, 1H), 7.95 (d, J=8.4Hz, 1H), 7.59-7.57 (m, 1H), 7.55-7.53 (m, 1H), 7.29 (d, J=7.2Hz, 1H), 7.00 (d, J=7.8Hz, 1H), 4.70 (t, J=7.8Hz, 2H), 3.74 (t, J=7.8Hz, 2H), 3.08 (s, br, 8H), 1.51 (s, 9H)
The synthesis of step 5) 4- (4- (2- amido ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
4- (4- (2- nitro-ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (4.2g, 10.9mmol) is dissolved in methanol The in the mixed solvent of (24mL) and tetrahydrofuran (3mL), then Pd/C (420mg) is added thereto, then reaction solution is in H2 In (1atm) atmosphere, overnight in reaction under room temperature.After reaction, reaction mixture is filtered to remove Pd/C, then will Filtrate decompression is spin-dried for obtaining crude product.Crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=30/1), concentration It is yellow solid (3.2g, 82.7%) that title compound is obtained after drying.
MS(ESI,pos.ion)m/z:356.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.26-8.25 (m, 1H), 8.03 (d, J=7.8Hz, 1H), 7.51- 7.47 (m, 2H), 7.30 (d, J=7.8Hz, 1H), 6.97 (d, J=7.8Hz, 1H), 4.16 (brs, 8H), 3.36 (t, J= 7.8Hz, 2H), 3.20 (t, J=7.8Hz, 2H), 1.50 (s, 9H)
The synthesis of step 6) 4- (4- (2- (benzenesulfonamido-) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (210mg, 0.59mmol), benzene sulfonyl chloride (125mg, 0.71mmol) He Sanyi Crude product is prepared in amine (0.16mL, 1.18mmol) reaction in methylene chloride (6mL), and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be faint yellow solid (266mg, 90.8%).
MS(ESI,pos.ion)m/z:496.2[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):8.21-8.19(m,1H),7.89-7.87(m,1H),7.83(t,J =5.4Hz, 1H), 7.81 (s, 1H), 7.80 (d, J=1.8Hz, 1H), 7.65-7.62 (m, 1H), 7.59-7.57 (m, 2H), 7.54-7.50 (m, 2H), 7.25 (d, J=7.6Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 3.11-3.08 (m, 4H), 3.04- 2.94(m,8H),1.44(s,9H).
The synthesis of step 7) N- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
By 4- (4- (2- (benzenesulfonamido-) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (266mg, 0.54mmol) It is dissolved in ethyl acetate (10mL), then the ethyl acetate solution (5mL, 3M) of hydrogen chloride is added thereto, then reaction solution is in room Temperature is lower to react 2h.After reaction, reaction mixture decompression is spin-dried for, saturated sodium carbonate solution (40mL) is added in residue, Then with methylene chloride (50mL) extraction and saturated salt solution (40mL) washing.After liquid separation, organic phase is dry with anhydrous sodium sulfate Dry, filtering, then filtrate is depressurized and spin-dried obtains title compound as yellow solid (200mg, 94.3%).
MS(ESI,pos.ion)m/z:396.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.18-8.17(m,1H),7.88-7.85(m,1H),7.82-7.80 (m, 2H), 7.65-7.55 (m, 3H), 7.51-7.48 (m, 2H), 7.24 (d, J=7.6Hz, 1H), 7.00 (d, J=7.6Hz, 1H),3.11-3.07(m,2H),3.04-3.01(m,2H),2.96-2.95(m,4H),2.90(brs,4H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):149.6,140.9,132.8,129.7,129.0,127.4, 127.0,126.4,125.4,124.6,124.2,114.8,54.7,46.5,44.0,32.9.
The synthesis of the fluoro- N- of 38 2- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The synthesis of step 1) 4- (4- (2- (2- fluorobenzene sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 2- fluorophenylsulfonyl chloride (132mg, 0.68mmol) and Crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is through silica gel column chromatography Purify (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (260mg, 90.0%).
MS(ESI,pos.ion)m/z:514.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.21-8.19(m,1H),8.14-8.12(m,1H),7.90-7.88 (m, 1H), 7.79 (td, J=7.8,1.6Hz, 1H), 7.71-7.65 (m, 1H), 7.55-7.50 (m, 2H), 7.43-7.39 (m, 1H), 7.35 (td, J=7.6,1.2Hz, 1H), 7.24 (d, J=7.7Hz, 1H), 7.04 (d, J=7.6Hz, 1H), 3.60 (brs,4H),3.17-3.09(m,4H),2.93(brs,4H),1.44(s,9H).
The synthesis of the fluoro- N- of step 2) 2- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (2- Fluorobenzene sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (260mg, 0.51mmol) is in ethyl acetate (10mL) Crude product is prepared in reaction, and it is white solid (200mg, 95.5%) that title compound is obtained after the concentrated drying of crude product.
MS(ESI,pos.ion)m/z:414.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.19-8.16(m,1H),7.88-7.86(m,1H),7.80(td,J =7.6,1.6Hz, 1H), 7.71-7.65 (m, 1H), 7.52-7.48 (m, 2H), 7.43-7.39 (m, 1H), 7.36 (t, J= 8.0Hz, 1H), 7.23 (d, J=7.6Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 3.16-3.11 (m, 4H), 3.00-2.89 (m,8H)；
13C NMR(100MHz,DMSO-d6) δ (ppm): 158.7 (d, J=251.9Hz), 149.6,135.7 (d, J= 8.6Hz), 132.8,130.1,129.5,129.0,128.9,127.4,126.4,125.4,125.3 (d, J=3.6Hz), (124.6,124.2,117.7 d, J=21Hz), 114.8,54.6,46.5,43.9,33.1.
The synthesis of the chloro- N- of 39 2- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The synthesis of step 1) 4- (4- (2- (2- chlorobenzenesulfonyl amino) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 2- chlorobenzene sulfonyl chloride (143mg, 0.68mmol) and Crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is through silica gel column chromatography Purify (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (251mg, 84.2%).
MS(ESI,pos.ion)m/z:530.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.20-8.17 (m, 1H), 8.08 (t, J=5.12Hz, 1H), 7.97 (dd, J=8.0,1.2Hz, 1H), 7.86-7.82 (m, 1H), 7.66-7.59 (m, 2H), 7.53-7.48 (m, 3H), 7.22 (d, J =7.6Hz, 1H), 7.03 (d, J=7.6Hz, 1H), 3.59 (brs, 4H), 3.16-3.08 (brs, 4H), 2.92 (brs, 4H), 1.44(s,9H).
The synthesis of the chloro- N- of step 2) 2- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (2- Chlorobenzenesulfonyl amino) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (251mg, 0.47mmol) is in ethyl acetate (10mL) Crude product is prepared in reaction, and it is white solid (198mg, 97.3%) that title compound is obtained after the concentrated drying of crude product.
MS(ESI,pos.ion)m/z:430.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.18-8.14 (m, 1H), 7.98 (dd, J=7.6,1.2Hz, 1H), 7.84-7.81 (m, 1H), 7.65-7.59 (m, 2H), 7.52-7.47 (m, 3H), 7.21 (d, J=7.6Hz, 1H), 6.97 (d, J =7.6Hz, 1H), 3.15-3.06 (m, 4H), 2.97-2.96 (m, 4H), 2.89 (brs, 4H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):149.5,138.5,134.4,132.8,132.2,131.2, 130.9,129.5,129.0,128.1,127.4,126.5,125.4,124.6,124.1,114.8,54.4,46.4,43.9, 33.1.
The synthesis of the bromo- N- of 40 2- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The synthesis of step 1) 4- (4- (2- (2- bromophenylsulfonyl amino) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 2- bromobenzene sulfonyl chloride (173mg, 0.68mmol) and Crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is through silica gel column chromatography Purify (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (298mg, 92.2%).
MS(ESI,pos.ion)m/z:574.1[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.20-8.18 (m, 1H), 8.06 (t, J=5.4Hz, 1H), 8.00 (dd, J=7.8,1.8Hz, 1H), 7.86-7.82 (m, 2H), 7.56-7.50 (m, 4H), 7.22 (d, J=7.8Hz, 1H), 7.03 (d, J=7.8Hz, 1H), 3.77 (brs, 4H), 3.15-3.10 (m, 4H), 2.92 (brs, 4H), 1.44 (s, 9H)
The synthesis of the bromo- N- of step 2) 2- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (2- Bromophenylsulfonyl amino) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (298mg, 0.52mmol) is in ethyl acetate (10mL) Crude product is prepared in reaction, and it is white solid (230mg, 93.5%) that title compound is obtained after the concentrated drying of crude product.
MS(ESI,pos.ion)m/z:474.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.18-8.15 (m, 1H), 8.01 (dd, J=8.0,2.0Hz, 1H), 7.85-7.81 (m, 2H), 7.57-7.47 (m, 4H), 7.21 (d, J=7.6Hz, 1H), 6.97 (d, J=7.6Hz, 1H), 3.16- 3.09(m,4H),2.96-2.95(m,4H),2.89(brs,4H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):149.5,140.2,135.8,134.3,132.8,131.0, 129.5,129.0,128.6,127.4,126.5,125.4,124.6,124.2,119.7,114.8,54.44,46.4,44.0, 33.2.
The synthesis of the fluoro- N- of 41 3- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The synthesis of step 1) 4- (4- (2- (3- fluorobenzene sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 3- fluorophenylsulfonyl chloride (132mg, 0.68mmol) and Crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is through silica gel column chromatography Purify (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (224mg, 77.5%).
MS(ESI,pos.ion)m/z:514.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.22-8.19 (m, 1H), 7.96 (t, J=5.6Hz, 1H), 7.92- 7.89 (m, 1H), 7.66-7.60 (m, 2H), 7.58-7.47 (m, 4H), 7.27 (d, J=7.6Hz, 1H), 7.06 (d, J= 7.6Hz,1H),3.58(brs,4H),3.13-3.05(m,4H),2.93(brs,4H),1.44(s,9H).
The synthesis of the fluoro- N- of step 2) 3- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (3- Fluorobenzene sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (224mg, 0.44mmol) is in ethyl acetate (10mL) Crude product is prepared in reaction, and it is white solid (170mg, 94.3%) that title compound is obtained after the concentrated drying of crude product.
MS(ESI,pos.ion)m/z:414.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.19-8.17(m,1H),7.89-7.87(m,1H),7.63-7.62 (m, 2H), 7.57 (d, J=8.4Hz, 1H), 7.52-7.49 (m, 3H), 7.25 (d, J=7.6Hz, 1H), 7.01 (d, J= 7.6Hz,1H),3.11-3.09(m,4H),2.96-2.90(m,8H)；
13C NMR(100MHz,DMSO-d6) δ (ppm): 162.2 (d, J=246.8Hz), 149.6,143.1 (d, J= 6.7Hz), 132.8,132.1 (d, J=8.0Hz), 129.6,129.0,127.4,126.4,125.4,124.6,124.2, 123.2 (d, J=2.8Hz), 120.0 (d, J=21.1Hz), 114.8,113.9 (d, J=24Hz), 54.6,46.5,43.9, 33.1.
The synthesis of the chloro- N- of 42 3- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The synthesis of step 1) 4- (4- (2- (3- chlorobenzenesulfonyl amino) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 3- chlorobenzene sulfonyl chloride (143mg, 0.68mmol) and Crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is through silica gel column chromatography Purify (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (244mg, 81.8%).
MS(ESI,pos.ion)m/z:530.2[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.21-8.20 (m, 1H), 7.98 (t, J=5.4Hz, 1H), 7.90 (dd, J=6.5,2.9Hz, 1H), 7.80 (d, J=1.7Hz, 1H), 7.74 (d, J=7.8Hz, 1H), 7.72-7.70 (m, 1H), (7.60 t, J=7.8Hz, 1H), 7.55-7.51 (m, 2H), 7.26 (d, J=7.6Hz, 1H), 7.06 (d, J=7.6Hz, 1H), 3.70(brs,4H),3.11-3.10(m,2H),3.07-3.05(m,2H),2.94(brs,4H),1.44(s,9H).
The synthesis of the chloro- N- of step 2) 3- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (3- Chlorobenzenesulfonyl amino) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (244mg, 0.46mmol) is in ethyl acetate (10mL) Crude product is prepared in reaction, and it is white solid (177mg, 89.4%) that title compound is obtained after the concentrated drying of crude product.
MS(ESI,pos.ion)m/z:430.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.20-8.17(m,1H),7.90-7.87(m,1H),7.81(s, 1H), 7.75 (d, J=8.0Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.60 (t, J=8.0Hz, 1H), 7.51-7.49 (m, 2H), 7.25 (d, J=7.6Hz, 1H), 7.00 (d, J=7.6Hz, 1H), 3.09 (brs, 4H), 2.97 (brs, 4H), 2.91 (brs,4H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):149.5,142.9,134.3,132.9,132.8,131.7, 129.6,129.0,127.4,126.6,126.4,125.7,125.4,124.6,124.2,114.8,54.5,46.4,43.9, 32.9.
The synthesis of 43 4- methoxyl group-N- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The conjunction of step 1) 4- (4- (2- (4- methoxybenzene sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester At
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 4- Methoxybenzenesulfonyl chloride (140mg, 0.68mmol) and crude product, crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL) It is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1), it is solid for white that title compound is obtained after concentrate drying Body (248mg, 82.5%).
MS(ESI,pos.ion)m/z:526.2[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):8.21-8.19(m,1H),7.89-7.87(m,1H),7.72(s, 1H), 7.71 (s, 1H), 7.66 (t, J=5.4Hz, 1H), 7.53-7.50 (m, 2H), 7.25 (d, J=7.8Hz, 1H), 7.09 (s, 1H), 7.07 (s, 1H), 7.05 (d, J=7.2Hz, 1H), 3.82 (brs, 7H), 3.10-3.07 (m, 2H), 3.00-2.71 (m,6H),1.44(s,9H).
The synthesis of step 2) 4- methoxyl group-N- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (4- Methoxybenzene sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (248mg, 0.47mmol) is in ethyl acetate Crude product is prepared in reaction in (10mL), obtained after the concentrated drying of crude product title compound be white solid (190mg, 94.6%).
MS(ESI,pos.ion)m/z:426.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.19-8.16(m,1H),7.88-7.85(m,1H),7.72(d,J =8.8Hz, 2H), 7.51-7.49 (m, 2H), 7.24 (d, J=7.6Hz, 1H), 7.08 (d, J=8.8Hz, 2H), 7.00 (d, J =7.6Hz, 1H), 3.82 (s, 3H), 3.10-3.06 (m, 2H), 3.00-2.90 (m, 10H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):162.6,149.5,132.9,132.6,129.8,129.1, 129.0,127.4,126.4,125.4,124.5,124.3,114.8,56.1,54.5,46.4,44.0,32.9.
The synthesis of the fluoro- N- of 44 4- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The synthesis of step 1) 4- (4- (2- (4- fluorobenzene sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 4- fluorophenylsulfonyl chloride (132mg, 0.68mmol) and Crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is through silica gel column chromatography Purify (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (251mg, 86.9%).
MS(ESI,pos.ion)m/z:514.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.22-8.18(m,1H),7.91-7.80(m,4H),7.55-7.50 (m, 2H), 7.42-7.37 (m, 2H), 7.26 (d, J=7.6Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 3.60 (brs, 4H), 3.12-3.08(m,2H),3.06-3.01(m,2H),2.93(brs,4H),1.44(s,9H).
The synthesis of the fluoro- N- of step 2) 4- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (4- Fluorobenzene sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (251mg, 0.49mmol) is in ethyl acetate (10mL) Crude product is prepared in reaction, and it is white solid (195mg, 96.5%) that title compound is obtained after the concentrated drying of crude product.
MS(ESI,pos.ion)m/z:414.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.19-8.17(m,1H),7.89-7.82(m,3H),7.51-7.49 (m, 2H), 7.39 (t, J=8.8Hz, 2H), 7.24 (d, J=7.6Hz, 1H), 7.00 (d, J=7.6Hz, 1H), 3.10-3.08 (m,2H),3.05-3.04(m,2H),2.96-2.89(m,8H)；
13C NMR(100MHz,DMSO-d6) δ (ppm): 164.5 (d, J=249.2Hz), 149.6,137.3 (d, J= 2.8Hz), 132.9,130.0,129.9,129.6,129.0,127.4,126.4,125.4,124.6,124.2,116.8, 116.6,114.8,54.6,46.5,44.0,32.9.
The synthesis of the chloro- N- of 45 4- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
The synthesis of step 1) 4- (4- (2- (4- chlorobenzenesulfonyl amino) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 4- chlorobenzene sulfonyl chloride (143mg, 0.68mmol) and Crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is through silica gel column chromatography Purify (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (250mg, 83.9%).
MS(ESI,pos.ion)m/z:530.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.22-8.19(m,1H),7.93-7.87(m,2H),7.78-7.75 (m, 2H), 7.63-7.61 (m, 2H), 7.55-7.50 (m, 2H), 7.26 (d, J=7.6Hz, 1H), 7.05 (d, J=7.6Hz, 1H),3.59(brs,4H),3.13-3.03(m,4H),2.93(brs,4H),1.44(s,9H).
The synthesis of the chloro- N- of step 2) 4- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (4- Chlorobenzenesulfonyl amino) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (250mg, 0.47mmol) is in ethyl acetate (10mL) Crude product is prepared in reaction, and it is white solid (200mg, 98.5%) that title compound is obtained after the concentrated drying of crude product.
MS(ESI,pos.ion)m/z:430.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.20-8.16(m,1H),7.89-7.85(m,1H),7.78(s, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.52-7.47 (m, 2H), 7.24 (d, J=7.6Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 3.12-3.03 (m, 4H), 2.96-2.95 (m, 4H), 2.90 (brs, 4H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):149.5,139.8,137.8,132.8,129.7,129.6, 129.0,128.9,127.4,126.4,125.4,124.6,124.2,114.8,54.4,40.2,39.9,32.9.
The synthesis of fluoro- N- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide of 46 2,6- of embodiment bis-
The conjunction of step 1) 4- (4- (2- (2,6- difluoro benzenesulfonamido-) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester At
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 2,6- difluoro chloride (144mg, 0.68mmol) and crude product, crude product is prepared in triethylamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL) It is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1), it is solid for white that title compound is obtained after concentrate drying Body (270mg, 90.3%).
MS(ESI,pos.ion)m/z:532.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.43 (t, J=5.4Hz, 1H), 8.21-8.19 (m, 1H), 7.95- 7.93 (m, 1H), 7.69-7.62 (m, 1H), 7.55-7.50 (m, 2H), 7.28-7.20 (m, 3H), 7.04 (d, J=7.6Hz, 1H),3.61(brs,4H),3.27-3.22(m,2H),3.17-3.13(m,2H),2.93(brs,4H),1.44(s,9H).
The synthesis of the fluoro- N- of step 2) 2,6- bis- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) benzsulfamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (2, 6- difluoro benzenesulfonamido-) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (270mg, 0.51mmol) is in ethyl acetate Crude product is prepared in reaction in (10mL), obtained after the concentrated drying of crude product title compound be white solid (218mg, 99.5%).
MS(ESI,pos.ion)m/z:432.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.19-8.16(m,1H),7.93-7.91(m,1H),7.70-7.62 (m, 1H), 7.53-7.48 (m, 2H), 7.26-7.21 (m, 3H), 6.99 (d, J=7.6Hz, 1H), 3.25-3.22 (m, 2H), 3.16-3.13(m,2H),2.96-2.95(m,4H),2.90(brs,4H)；
13C NMR(100MHz,DMSO-d6) δ (ppm): 160.2 (d, J=4.4Hz), 157.7 (d, J=4.3Hz), (149.5,135.4 t, J=11Hz), 132.8,129.5,129.0,127.4,126.4,125.4,124.6,124.2,118.8 (t, J=16.5Hz), 114.8,113.9 (d, J=3.3Hz), 113.7 (d, J=3.4Hz), 54.5,40.2,39.8,33.0.
The synthesis of 47 N- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) naphthalene -1- sulfonamide
The synthesis of step 1) 4- (4- (2- (naphthalene -1- sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 1- naphthalene sulfonyl chloride (153mg, 0.68mmol) and three Crude product is prepared in ethamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is pure through silica gel column chromatography Change (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (269mg, 87.6%).
MS(ESI,pos.ion)m/z:546.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.66 (d, J=8.4Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 8.20-8.14 (m, 3H), 8.11-8.09 (m, 1H), 7.74-7.61 (m, 4H), 7.41-7.44 (m, 2H), 7.12 (d, J= 7.6Hz 1H), 6.95 (d, J=7.6Hz, 1H), 3.58 (brs, 4H), 3.10-3.05 (m, 2H), 3.01-2.98 (m, 2H), 2.89(brs,4H),1.44(s,9H).
The synthesis of step 2) N- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) naphthalene -1- sulfonamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (naphthalene -1- sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (269mg, 0.49mmol) is at ethyl acetate (10mL) Crude product is prepared in middle reaction, obtained after the concentrated drying of crude product title compound be white solid (210mg, 95.4%).
MS(ESI,pos.ion)m/z:446.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.68 (d, J=8.4Hz, 1H), 8.21 (d, J=8.0Hz, 1H), 8.14 (t, J=8.4Hz, 2H), 8.08 (d, J=7.6Hz, 1H), 7.74-7.67 (m, 3H), 7.62 (t, J=8.0Hz, 1H), (7.48-7.41 m, 2H), 7.09 (d, J=7.6Hz, 1H), 6.88 (d, J=7.6Hz, 1H), 3.09-3.05 (m, 2H), 2.00- 2.98(m,2H),2.94-2.93(m,4H),2.86(brs,4H)；13C NMR(100MHz,DMSO-d6)δ(ppm):149.4, 136.1,134.4,134.2,132.7,129.5,129.4,129.0,128.9,128.3,128.1,127.4,127.3, 126.4,125.4,125.2,125.0,124.5,124.1,114.7,54.4,46.4,43.8,33.1.
The synthesis of 48 N- of embodiment (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) naphthalene -2- sulfonamide
The synthesis of step 1) 4- (4- (2- (naphthalene -2- sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 4- (4- (2- amido Ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (200mg, 0.56mmol), 2- naphthalene sulfonyl chloride (153mg, 0.68mmol) and three Crude product is prepared in ethamine (0.15mL, 1.13mmol) reaction in methylene chloride (6mL), and crude product is pure through silica gel column chromatography Change (petrol ether/ethyl acetate (v/v)=3/1), obtained after concentrate drying title compound be white solid (241mg, 78.5%).
MS(ESI,pos.ion)m/z:546.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.45 (d, J=1.2Hz, 1H), 8.17-8.15 (m, 2H), 8.12 (d, J=8.8Hz, 1H), 8.03 (d, J=8.0Hz, 1H), 7.92 (t, J=4.4Hz, 1H), 7.83-7.82 (m, 1H), 7.81- 7.80 (m, 1H), 7.72-7.64 (m, 2H), 7.49-7.45 (m, 1H), 7.43-7.38 (m, 1H), 7.24 (d, J=7.6Hz, 1H), 7.02 (d, J=7.6Hz, 1H), 3.59 (brs, 4H), 3.08 (brs, 4H), 2.91 (brs, 4H), 1.44 (s, 9H)
The synthesis of step 2) N- (2- (4- (piperazine -1- base) naphthalene -1- base) ethyl) naphthalene -2- sulfonamide
This step title compound method referring to described in 37 step 7 of embodiment is prepared, i.e., by 4- (4- (2- (naphthalene -2- sulfonamido) ethyl) naphthalene -1- base) piperazine -1- carboxylic acid tert-butyl ester (241mg, 0.44mmol) is at ethyl acetate (10mL) Crude product is prepared in middle reaction, obtained after the concentrated drying of crude product title compound be white solid (149mg, 75.5%).
MS(ESI,pos.ion)m/z:446.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 8.46 (d, J=1.2Hz, 1H), 8.16-8.11 (m, 3H), 8.03 (d, J=8.0Hz, 1H), 7.95 (s, br, NH), 7.82 (dd, J=8.8,2.0Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.72-7.64 (m, 2H), 7.47-7.43 (m, 1H), 7.41-7.37 (m, 1H), 7.23 (d, J=7.6Hz, 1H), 6.98 (d, J =7.6Hz, 1H), 3.07 (brs, 4H), 3.02-2.99 (m, 4H), 2.91 (brs, 4H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):149.2,137.9,134.6,132.8,132.2,129.8, 129.6,129.1,128.9,128.3,128.0,127.9,127.4,126.4,125.4,124.5,124.2,122.7, 114.5,53.8,46.1,44.0,32.9.
49 1- of embodiment (2- methoxyl group -5- (N- (2- methyl -2- (naphthalene -1- base) propyl) sulfamoyl) phenyl) piperazine The synthesis of 1- oxide
Step 1) 1- (2- methoxyl group -5- (N- (2- methyl -2- (naphthalene -1- base) propyl) sulfamoyl) phenyl) -4- (2,2, 2- trichloroacetyl) piperazine 1- oxide synthesis
At 25 DEG C, by 4- methoxyl group-N- (2- methyl -2- (naphthalene -1- base) propyl) -3- (4- (2,2,2- tribromo-acetyls Base) piperazine -1- base) benzsulfamide (808mg, 1.35mmol) is dissolved in the mixed liquor of acetone (15.0mL) and water (5.0mL), connects Sequentially add sodium bicarbonate solid (168mg, 2.0mmol) and ammonium persulfate-sodium bisulfate (1.24g, 2.0mmol), then make Reaction solution is stirred to react 3 hours.After reaction, water (40mL) quenching reaction is added into reaction mixture, then uses acetic acid Ethyl ester (40mL) extraction.After liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate is depressurized and spin-dried up to pale yellow colored solid Body product (800mg, 96.5%).
MS(ESI,pos.ion)m/z:614.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 9.20 (d, J=2.2Hz, 1H), 8.34-8.25 (m, 1H), 7.84 (dd, J=6.1,3.5Hz, 1H), 7.75 (dd, J=8.6,2.1Hz, 1H), 7.71 (d, J=8.0Hz, 1H), 7.47 (d, J= 7.0Hz, 1H), 7.40 (dd, J=8.7,4.1Hz, 3H), 6.96 (d, J=8.7Hz, 1H), 4.59-4.38 (m, 4H), 4.02 (s, 3H), 3.49 (d, J=6.6Hz, 2H), 3.32 (brs, 2H)
Step 2) 1- (2- methoxyl group -5- (N- (2- methyl -2- (naphthalene -1- base) propyl) sulfamoyl) phenyl) piperazine 1- oxygen The synthesis of compound
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 1- (2- methoxyl group- 5- (N- (2- methyl -2- (naphthalene -1- base) propyl) sulfamoyl) phenyl) -4- (2,2,2- trichloroacetyl) piperazine 1- oxide (780mg, 1.27mmol), potassium hydroxide (140mg, 2.5mmol are made into 1mmol/mL aqueous solution) are in tetrahydrofuran (20mL) Crude product is prepared in reaction, and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is concentrated and dried After obtain title compound be white solid (443mg, 74.1%).
MS(ESI,pos.ion)m/z:470.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 9.15 (s, 1H), 8.27 (d, J=9.2Hz, 1H), 7.87-7.83 (m, 1H), 7.72 (d, J=8.1Hz, 1H), 7.69 (dd, J=8.5,2.0Hz, 1H), 7.48 (d, J=7.3Hz, 1H), 7.44- 7.35 (m, 3H), 6.92 (d, J=8.6Hz, 1H), 4.58 (t, J=10.3Hz, 2H), 4.04 (s, 3H), 3.90 (t, J= 11.5Hz,2H),3.52(s,2H),3.03-2.97(m,4H),1.63(s,6H)；
13C NMR(150MHz,CDCl3)δ(ppm):153.3,141.0,135.0,133.7,131.2,130.1,129.8, 128.4,125.8,125.6,125.3,125.1,124.8,124.1,112.4,64.5,56.5,52.6,40.7,40.3, 27.8.
50 N- of embodiment (2- (6- hydroxyl naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulphur The synthesis of amide
The synthesis of step 1) 6- ((triisopropylsilyl) oxygroup) -3,4- dihydronaphthalene -1 (2H) -one
At 25 DEG C, by 6- hydroxyl -3,4- dihydronaphthalene -1 (2H) -one (3.0g, 18.5mmol) and imidazoles (3.15g, 45.8mmol) be dissolved in methylene chloride (40mL), be then slowly added dropwise into above-mentioned solution tri isopropyl chlorosilane (4.8mL, 98.18mmol), it is stirred to react reaction solution 19 hours.After reaction, reaction mixture decompression is spin-dried for removing molten Agent obtains crude product.Title compound is obtained after crude by column chromatography purifying (petrol ether/ethyl acetate (v/v)=10/1) For pale tan oil (5.8g, 98%).
MS(ESI,pos.ion)m/z:319.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.94 (d, J=8.6Hz, 1H), 6.77 (dd, J=8.6,2.3Hz, 1H), 6.68 (d, J=2.0Hz, 1H), 2.88 (t, J=6.1Hz, 2H), 2.59 (t, J=6.3Hz, 2H), 2.15-2.06 (m, 2H),1.31-1.23(m,3H),1.11-1.09(m,18H).
The synthesis of step 2) 2- (6- ((triisopropylsilyl) oxygroup) -3,4- dihydronaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 6- ((triisopropyl Silicon substrate) oxygroup) -3,4- dihydronaphthalene -1 (2H) -one (5.8g, 18mmol), 2- cyanoacetic acid (3.25g, 38.2mmol), enanthic acid Crude product is prepared in reaction in (50mL) in toluene for (0.65mL, 4.6mmol) and benzylamine (0.5mL, 5.0mmol), thick to produce Object is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), and title compound is obtained after concentrate drying as white Solid (4.28g, 69%).
MS(ESI,pos.ion)m/z:342.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.00-6.87 (m, 1H), 6.74-6.67 (m, 2H), 6.11 (t, J= 4.5Hz, 1H), 3.44 (d, J=1.6Hz, 2H), 2.73 (t, J=8.1Hz, 2H), 2.35-2.30 (m, 2H), 1.32-1.21 (m,3H),1.11-1.10(m,18H).
The synthesis of step 3) 2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., at 25 DEG C, by 2- (6- ((triisopropylsilyl) oxygroup) -3,4- dihydronaphthalene -1- base) acetonitrile (1.0g, 2.93mmol) and DDQ (681mg, 3.0mmol) crude product is prepared in reaction in methylene chloride (30mL), and crude product is purified by silica gel column chromatography (petroleum ether/second Acetoacetic ester (v/v)=60/1), it is colorless oil (427mg, 43%) that title compound is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:340.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.75 (d, J=9.0Hz, 1H), 7.70 (d, J=7.7Hz, 1H), 7.43 (d, J=6.1Hz, 1H), 7.42-7.37 (m, 1H), 7.28 (d, J=2.3Hz, 1H), 7.24 (dd, J=9.1,2.5Hz, 1H),4.09(s,2H),1.37-1.33(m,3H),1.15-1.13(m,18H).
The synthesis of step 4) 2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propionitrile
This step title compound method referring to described in 13 step 1 of embodiment is prepared, i.e., by 2-, (((three is different by 6- Propyl silicon substrate) oxygroup) naphthalene -1- base) acetonitrile (0.42g, 1.24mmol), sodium hydride (60% is dispersed in mineral oil, 0.15g, 5.9mmol) and crude product is prepared in iodomethane (0.3mL, 5.0mmol) reaction in anhydrous DMF (5mL), and crude product is through silicon Gel column chromatography eluting (petrol ether/ethyl acetate (v/v)=60/1), it is colorless oil that title compound is obtained after concentrate drying (160mg, 33%).
MS(ESI,pos.ion)m/z:368.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.42 (d, J=9.1Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.37 (t, J=7.7Hz, 1H), 7.32 (d, J=6.5Hz, 1H), 7.28 (t, J=2.2Hz, 1H), 7.24 (d, J=2.6Hz, 1H),1.96(s,6H),1.34-1.30(m,3H),1.16-1.14(m,18H).
The synthesis of step 5) (2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propyl) carboxylic acid tert-butyl ester
At 25 DEG C, by 2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propionitrile (0.35g, It 0.95mmol) is added in tetrahydrofuran (10mL) with di-tert-butyl dicarbonate (0.26mL, 1.1mmol), is subsequently added into thunder Buddhist nun Nickel (150mg) reacts reaction solution 47 hours under 1.5MPa Hydrogen Vapor Pressure.After reaction, by reaction mixture mistake Catalyst is filtered out, then filtrate is depressurized and spin-dried obtains crude product.Crude by column chromatography purifies (petrol ether/ethyl acetate (v/v)=50/1 it is colorless oil (394mg, 88%) that title compound is obtained after).
MS(ESI,pos.ion)m/z:494.2[M+Na]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.32 (d, J=9.4Hz, 1H), 7.60 (d, J=7.7Hz, 1H), 7.36-7.30 (m, 2H), 7.25 (d, J=2.6Hz, 1H), 7.15 (dd, J=9.1,2.0Hz, 1H), 3.75 (d, J=6.1Hz, 2H),1.58(s,6H),1.39(s,9H),1.33-1.30(m,3H),1.15-1.14(m,18H).
The synthesis of step 6) 2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propane -1- amine
In the case where 0 DEG C of low temperature is bathed, by (2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propyl) carboxylic acid uncle Butyl ester (0.335g, 0.71mmol) is dissolved in methylene chloride (3mL), is subsequently added into trifluoroacetic acid (3mL), is then made reaction solution anti- It answers 40 minutes.After reaction, reaction mixture is carried out decompression to be spin-dried for, methylene chloride (30mL) is added in residue, then It is washed with saturated sodium bicarbonate solution (40mL х 2).After liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, by filtrate decompression It is colorless oil (224mg, 85%) that title compound is obtained after being spin-dried for.
MS(ESI,pos.ion)m/z:372.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.15 (d, J=9.4Hz, 1H), 7.56 (dd, J=5.8,3.3Hz, 1H), 7.30 (d, J=2.4Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=2.5Hz, 1H), 7.13 (dd, J=9.3,2.6Hz, 1H),3.33(s,2H),1.60(s,6H),1.37-1.22(m,3H),1.15-1.13(m,18H).
Step 7) 4- methoxyl group-N- (2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propane -1- amine (260mg, 0.7mmol), 4- methoxyl group -3- (4- (2,2,2- tri- Chloracetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (366mg, 0.84mmol) and triethylamine (0.5mL, 3.0mmol) be in dichloromethane Crude product is prepared in reaction in alkane (10mL), and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/ 1) it is faint yellow solid (398mg, 74%) that title compound, is obtained after concentrate drying.MS(ESI,pos.ion)m/z:770.1 [M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.91 (d, J=9.4Hz, 1H), 7.59 (d, J=7.9Hz, 1H), 7.32 (t, J=7.7Hz, 1H), 7.28 (s, 1H), 7.24 (d, J=2.2Hz, 1H), 7.22 (d, J=2.6Hz, 1H), 7.10 (d, J=2.1Hz, 1H), 6.93 (dd, J=9.4,2.7Hz, 1H), 6.78 (d, J=8.6Hz, 1H), 3.93 (s, 3H), 3.83 (t, J=4.7Hz, 2H), 3.75 (t, J=3.6Hz, 2H), 3.45 (d, J=6.3Hz, 2H), 3.02 (brs, 4H), 1.57 (s, 8H),1.34-1.24(m,3H),1.13-1.11(m,18H).
Step 8) 4- methoxyl group-N- (2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propyl) -3- (piperazine Piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by 4- methoxyl group-N- (2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propyl) -3- (4- (2,2,2- trichloroacetyl) piperazine -1- Base) benzsulfamide (385mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/mL aqueous solution) is in tetrahydro furan Crude product is prepared in (10mL) middle reaction of muttering, and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/ 1) it is white solid (264mg, 84%) that title compound, is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:626.5[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.96 (d, J=9.4Hz, 1H), 7.59 (d, J=7.9Hz, 1H), 7.32 (t, J=7.7Hz, 1H), 7.28 (s, 1H), 7.25-7.23 (m, 1H), 7.22 (s, 1H), 7.17 (d, J=2.1Hz, 1H), 6.98 (dd, J=9.4,2.7Hz, 1H), 6.76 (d, J=8.5Hz, 1H), 3.91 (s, 3H), 3.45 (s, 2H), 3.05- 3.03(m,4H),2.97-2.96(m,4H),1.56(s,6H),1.33-1.28(m,3H),1.14-1.12(m,18H).
Step 9) N- (2- (6- hydroxyl naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide Synthesis
At 25 DEG C, by 4- methoxyl group-N- (2- methyl -2- (6- ((triisopropylsilyl) oxygroup) naphthalene -1- base) propyl) - 3- (piperazine -1- base) benzsulfamide (0.11g, 0.17mmol) is dissolved in tetrahydrofuran (5mL), is subsequently added into tetrabutyl ammonium fluoride Tetrahydrofuran solution (0.18mL, 1mmol/mL), be stirred to react reaction solution 30 minutes.After reaction, it will react Mixture carries out decompression and is spin-dried for, and obtains crude product, crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/ 1) it is white solid (78mg, 95%) that title compound, is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:470.2[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.12 (d, J=9.4Hz, 1H), 7.55 (d, J=8.1Hz, 1H), 7.46 (t, J=5.9Hz, 1H), 7.34 (dd, J=8.5,2.0Hz, 1H), 7.27 (t, J=7.7Hz, 1H), 7.24 (d, J= 2.0Hz, 1H), 7.20 (d, J=7.3Hz, 1H), 7.12 (d, J=2.6Hz, 1H), 7.04 (dd, J=9.4,2.6Hz, 1H), 7.01 (d, J=8.6Hz, 1H), 5.75 (s, 1H), 3.81 (s, 3H), 3.12 (d, J=5.5Hz, 2H), 2.87-2.86 (m, 8H),1.47(s,6H)；
13C NMR(150MHz,DMSO-d6)δ(ppm):155.2,154.5,142.5,142.1,137.0,132.8, 127.8,126.8,125.9,125.7,122.1,121.9,117.8,116.4,111.7,111.0,56.2,55.4,52.6, 51.1,45.7,27.8.
51 N- of embodiment (2- (7- hydroxyl naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulphur The synthesis of amide
The synthesis of -1 (2H) -one of step 1) 7- (benzyloxy) -3,4- dihydronaphthalene
At 25 DEG C, by 7- hydroxyl -3,4- dihydronaphthalene -1 (2H) -one (3.00g, 18.5mmol) and potassium carbonate (5.11g, It 37.0mmol) is added in DMF (20mL), cylite (2.42mL, 20.4mmol) then is added thereto, then makes reaction solution It is stirred to react 9 hours.After reaction, reaction solution is added drop-wise in ice water (200mL), there is solid precipitation, after filtering, being dry i.e. Obtaining title compound is white solid (4.63g, 99.2%).
MS(ESI,pos.ion)m/z:253.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.64 (d, J=2.8Hz, 1H), 7.46 (d, J=7.2Hz, 2H), 7.41 (t, J=7.2Hz, 2H), 7.37-7.33 (m, 1H), 7.20 (d, J=8.4Hz, 1H), 7.15 (dd, J=8.4,2.8Hz, 1H), 5.12 (s, 2H), 2.93 (t, J=6.0Hz, 2H), 2.67 (t, J=6.0Hz, 2H), 2.19-2.09 (m, 2H)
The synthesis of step 2) 2- (7- (benzyloxy) -3,4- dihydronaphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 7- (benzyloxy)- 3,4- dihydronaphthalene -1 (2H) -one (4.62g, 18.3mmol), 2- cyanoacetic acid (2.35g, 27.6mmol), enanthic acid (0.65mL, It 4.6mmol) is reacted in (50mL) in toluene and crude product is prepared with benzylamine (0.5mL, 5.0mmol), crude product is through silica gel Column chromatographic purifying (petroleum ether/methylene chloride (v/v)=1/2), it is white solid that title compound is obtained after concentrate drying (4.7g, 93.2%).
1H NMR(400MHz,CDCl3) δ (ppm): 7.46 (d, J=7.2Hz, 2H), 7.41 (t, J=7.2Hz, 2H), 7.35 (t, J=7.2Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 6.83 (dd, J=8.4,2.4Hz, 1H), 6.77 (d, J= 2.4Hz, 1H), 6.31 (t, J=4.4Hz, 1H), 5.09 (s, 2H), 3.46 (d, J=1.6Hz, 2H), 2.75 (t, J=8.0Hz, 2H),2.40-2.32(m,2H).
The synthesis of step 3) 2- (7- (benzyloxy) naphthalene -1- base) acetonitrile
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., at 25 DEG C, by 2- (7- (benzyloxy) -3,4- dihydronaphthalene -1- base) acetonitrile (4.5g, 16.3mmol) and DDQ (4.5mg, 19.8mmol) are in dichloromethane Crude product is prepared in reaction in alkane (30mL), and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/ 1) it is rufous grease (4.41g, 98.7%) that title compound, is obtained after concentrate drying.
MS(ESI,pos.ion)m/z:274.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.85 (d, J=9.2Hz, 1H), 7.81 (d, J=8.4Hz, 1H), 7.57 (d, J=7.2Hz, 1H), 7.53 (d, J=7.2Hz, 2H), 7.45 (t, J=7.3Hz, 2H), 7.41-7.30 (m, 3H), 7.20 (d, J=1.6Hz, 1H), 5.25 (s, 2H), 4.04 (s, 2H)
The synthesis of step 4) 2- (7- (benzyloxy) naphthalene -1- base) -2- methyl propionitrile
This step title compound method referring to described in 13 step 1 of embodiment is prepared, i.e., by 2- (7- (benzyloxy Base) naphthalene -1- base) acetonitrile (4.41g, 16.1mmol), sodium hydride (60% is dispersed in mineral oil, 2.0g, 50mmol) and iodine first Crude product is prepared in alkane (3.5mL, 56.0mmol) reaction in anhydrous DMF (30mL), and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=20/1), obtained after concentrate drying title compound be faint yellow solid (3.75g, 77.1%).
MS(ESI,pos.ion)m/z:302.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.85-7.83 (m, 2H), 7.79 (d, J=8.0Hz, 1H), 7.57 (d, J=7.6Hz, 2H), 7.46-7.41 (m, 3H), 7.34-7.30 (m, 3H), 5.33 (s, 2H), 1.85 (s, 6H)
The synthesis of step 5) (2- (7- (benzyloxy) naphthalene -1- base) -2- methyl-propyl) carboxylic acid tert-butyl ester
At 25 DEG C, by 2- (7- (benzyloxy) naphthalene -1- base) -2- methyl propionitrile (1.9g, 6.3mmol) and two dimethyl dicarbonates Butyl ester (1.8mL, 7.8mmol) is added in tetrahydrofuran (10mL), is subsequently added into Raney's nickel (150mg), is then made reaction solution It is reacted 24 hours under 1.5MPa Hydrogen Vapor Pressure.After reaction, by reaction mixture Filtration of catalyst, then by filtrate Decompression is spin-dried for obtaining crude product.It is obtained after crude by column chromatography purifying (petrol ether/ethyl acetate (v/v)=10/1) titled Conjunction object is colorless oil (1.0g, 39.1%).
MS(ESI,pos.ion)m/z:306.0[M+H-100]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.85-7.79 (m, 2H), 7.71 (d, J=7.8Hz, 1H), 7.53 (d, J=7.2Hz, 2H), 7.45 (d, J=7.2Hz, 1H), 7.41 (t, J=7.2Hz, 2H), 7.36-7.29 (m, 2H), 7.27 (dd, J=8.4,1.8Hz, 1H), 5.33 (s, 2H), 3.70 (d, J=6.0Hz, 2H), 1.53 (s, 6H), 1.43 (s, 9H)
The synthesis of step 6) 2- (7- (benzyloxy) naphthalene -1- base) -2- methylpropane -1- amine
At 25 DEG C, by (2- (7- (benzyloxy) naphthalene -1- base) -2- methyl-propyl) carboxylic acid tert-butyl ester (0.88g, It 2.17mmol) is dissolved in methylene chloride (3mL), is subsequently added into trifluoroacetic acid (3mL), react reaction solution 40 minutes.Instead After answering, reaction mixture is subjected to decompression and is spin-dried for, methylene chloride (30mL) is added in residue, then uses unsaturated carbonate hydrogen Sodium solution (40mL х 2) washing.After liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate is depressurized and spin-dried is marked Topic compound is colorless oil (644mg, 97.0%).
MS(ESI,pos.ion)m/z:306.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 7.91-7.87 (m, 3H), 7.78 (d, J=8.0Hz, 1H), 7.57 (d, J=1.6Hz, 1H), 7.50 (d, J=7.2Hz, 2H), 7.45-7.36 (m, 3H), 7.33-7.27 (m, 3H), 5.28 (s, 2H),3.34(s,2H),1.54(s,6H).
Step 7) N- (2- (7- (benzyloxy) naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- (2,2,2- trichlorine Acetyl group) piperazine -1- base) benzsulfamide synthesis
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (7- (benzyloxy Base) naphthalene -1- base) -2- methylpropane -1- amine (610mg, 2.0mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine Piperazine -1- base) benzene -1- sulfonic acid chloride (1.24g, 2.84mmol) and triethylamine (0.67mL, 4.0mmol) be in methylene chloride (10mL) Crude product is prepared in reaction, and crude product is purified by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), is concentrated and dried After obtain title compound be faint yellow solid (785mg, 55.8%).
MS(ESI,pos.ion)m/z:704.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.80 (d, J=9.2Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.47-7.38 (m, 6H), 7.35 (d, J=6.8Hz, 1H), 7.33-7.29 (m, 2H), 7.21 (dd, J=8.8,2.0Hz, 1H), 7.02 (d, J=2.0Hz, 1H), 6.79 (d, J=8.4Hz, 1H), 4.98 (s, 2H), 3.87 (s, 3H), 3.80 (t, J= 4.8Hz, 2H), 3.71 (t, J=4.8Hz, 2H), 3.43 (d, J=6.4Hz, 2H), 2.97-2.93 (m, 4H), 1.54 (s, 6H)
Step 8) N- (2- (7- (benzyloxy) naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzene sulphur The synthesis of amide
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by N- (2- (7- (benzyl Oxygroup) naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzsulfamide (750mg, 1.06mmol), potassium hydroxide (168mg, 3.0mmol are made into 1mmol/mL aqueous solution) are in tetrahydrofuran (10mL) Crude product is prepared in reaction, and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), is concentrated and dried After obtain title compound be white solid (465mg, 83%).
MS(ESI,pos.ion)m/z:559.8[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.80 (d, J=9.2Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.47 (d, J=7.6Hz, 2H), 7.44-7.37 (m, 4H), 7.35-7.29 (m, 2H), 7.27-7.20 (m, 2H), 7.12 (d, J =2.4Hz, 1H), 6.76 (d, J=8.4Hz, 1H), 5.01 (s, 2H), 3.85 (s, 3H), 3.42 (s, 2H), 3.05-2.98 (m, 4H),2.92-2.90(m,4H),1.52(s,6H).
Step 9) N- (2- (7- hydroxyl naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- base) benzsulfamide Synthesis
At 25 DEG C, by N- (2- (7- (benzyloxy) naphthalene -1- base) -2- methyl-propyl) -4- methoxyl group -3- (piperazine -1- Base) benzsulfamide (0.53g, 0.95mmol) is dissolved in methanol (20mL), is subsequently added into Pd/C (200mg), then makes reaction solution It is reacted 12 hours under 1atm Hydrogen Vapor Pressure.After reaction, reaction mixture is filtered to remove Pd/C, then by filtrate decompression It is spin-dried for obtaining crude product.Crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), after concentrate drying It is white solid (200mg, 45%) to title compound.
MS(ESI,pos.ion)m/z:470.0[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 7.71 (d, J=8.8Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.52 (s, 1H), 7.33-7.26 (m, 3H), 7.21 (d, J=2.4Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 7.01 (dd, J =8.8,1.6Hz, 1H), 6.97 (d, J=8.8Hz, 1H), 3.79 (s, 3H), 3.14 (d, J=6.6Hz, 2H), 2.85 (s, 8H),1.44(s,6H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.1,154.5,141.7,139.1,132.5,131.9,131.0, 129.5,128.0,125.6,122.4,122.1,117.5,116.6,110.7,108.5,55.8,53.7,52.2,50.8, 45.6,27.7.
Biologic test
Embodiment A. radio ligand binding assay evaluates the compounds of this invention to the source of people 5- being expressed on CHO cells HT6The affinity of receptor
Using radio ligand binding assay evaluation the compounds of this invention to the source of people 5-HT being expressed on CHO cells6By The affinity of body, the specific steps are as follows:
The 32 μ g expression prepared there is into source of people 5-HT6The CHO cell membrane protein of receptor, 2nM radioactively labelled substance [3H] LSD, the compound of different test concentrations, 100 μM of 5-HT of addition (5-HT is for removing nonspecific binding site) and test Buffer is uniformly mixed, and mixed liquor is then incubated for 120min at 37 DEG C；Wherein, test buffer ingredient are as follows: 50mM Tris-HCl (pH 7.4), 10mM MgCl2, 0.5mM EDTA, 10 μM of Pargylines and 20mg/L protease inhibitors.
After incubation, glass fiber filter (GF/B, Packard) is used to filter under vacuum conditions above-mentioned mixed liquor, filter The filter membrane of device is first presoaked with 0.3%PEI before filtration.After filtering, filter membrane is rinsed several times with 50mM Tris-HCl.It is to be filtered After film is dry, the radioactivity of filter membrane is counted on scintillation counter (Topcount, Packard) with scintillation mixed solution.Wherein, Standard reference compounds are 5-HT, and are tested in each experiment multiple concentration to obtain its competition inhibition curve and calculate IC50。
The compounds of this invention is to the source of people 5-HT being expressed on CHO cells6The affinity measurement result of receptor is referring to Table A.
The affinity measurement result of Table A the compounds of this invention
Embodiment number IC50(nM) Embodiment number IC50(nM) Embodiment number IC50(nM)
Embodiment 1 2.7 Embodiment 11 2.1 Embodiment 25 16
Embodiment 2 0.92 Embodiment 12 0.17 Embodiment 26 3.2
Embodiment 3 31 Embodiment 13 1.3 Embodiment 27 5.0
Embodiment 4 11 Embodiment 15 11 Embodiment 28 2.1
Embodiment 5 4.1 Embodiment 17 1.1 Embodiment 29 2.3
Embodiment 6 1.3 Embodiment 18 1.4 Embodiment 31 1.2
Embodiment 7 1.0 Embodiment 21 1.7 Embodiment 33 5.5
Embodiment 8 0.5 Embodiment 22 0.31 Embodiment 34 2.6
Embodiment 9 0.69 Embodiment 23 3.7 Embodiment 35 1.6
Embodiment 10 0.28 Embodiment 24 2.0 Embodiment 36 0.46
By Table A it is found that the compounds of this invention is in 5-HT6Higher activity is generally shown in the affinity test of receptor.
Pharmacokinetic Evaluation of the embodiment B. dog after intravenous or stomach-filling quantify the compounds of this invention
1) animal subject:
Animal subject is dog, and concrete condition is as shown in table 2:
Table 2
Germline Grade Gender Quantity Weight Week old Source
Beagle dog Cleaning grade Male 6 8~10kg 6-7 weeks Beijing Ma this
2) analysis method:
The LC/MS/MS system of analysis includes the serial vacuum degassing machine of Agilent 1200, binary pump, and orifice plate is adopted automatically Sample device, thermostatted column compartment, charged spray ionize the triple level four bars mass spectrographs of Agilent G6430A in the source (ESI).Quantitative analysis It is carried out under MRM mode, wherein the parameter of MRM conversion is as shown in table 3:
Table 3
Fragmentation voltage 30V
Capillary voltage 140V
Dryer temperature 350℃
Atomizer 40psi
Drier flow velocity 9L/min
It is analyzed using waters XBridge C18 (2.1x 50mm, 3.5 μM of columns inject 5 μ L samples), analyzes item Part are as follows: mobile phase is that mobile phase is+0.1% formic acid (mobile phase A) of water+2mM ammonium formate and+0.1% first of methanol+2mM ammonium formate Sour (Mobile phase B), flow velocity 0.4mL/min, eluent gradient are as shown in table 4:
Table 4
Time The gradient of Mobile phase B
1.1min 5%
1.6min 95%
2.6min 95%
2.7min 5%
3.7min It terminates
3) experimental method
The intracorporal pharmcokinetic evaluation of dog is carried out to the compounds of this invention, the specific steps are as follows:
Experiment is divided into two groups, and one group is administered by intravenous injection, and one group passes through gastric infusion.By the compound of the present invention with The saline solution or 10%DMSO+10% of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline The form of Kolliphor HS 15+80% normal saline solution, is administered animal subject.For being injected intravenously administration group, Dosage is 1mg/kg, and then time point upon administration is 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 Venous blood sampling (0.3mL) when hour, and be centrifuged 10 minutes at 3,000 or 4,000rpm, plasma solutions are collected, and in -20 DEG C Or it is saved at -70 DEG C.For gastric infusion group, dosage 5mg/kg, then time point upon administration be 0.25,0.5, 1.0,2.0,4.0,6.0,8.0 and 24 hours when venous blood sampling (0.3mL), and be centrifuged 10 minutes at 3,000 or 4,000rpm, Plasma solutions are collected, and are saved at -20 DEG C or -70 DEG C.
The plasma solutions obtained are collected to above-mentioned each group carries out LC/MS/MS analysis.Analysis is the results show that chemical combination of the present invention Object is after gastric infusion in the intracorporal area under the drug-time curve AUC of doglastFor 1000~20000h*ng/mL, maximum plasma concentration CmaxFor 300~2000ng/mL；In the intracorporal elimination half-life period t of dog after intravenous administration administration1/2It is 1~6 hour, stable state table Sight distribution volume Vss is 0.5~25L/kg.Preferably, the compounds of this invention is after gastric infusion in the intracorporal AUC of doglastFor 14000~20000h*ng/mL, CmaxFor 1000~2000ng/mL；In the intracorporal t of dog after intravenous administration administration1/2For 4.5~ 6 hours, Vss was 0.5~3L/kg, and bioavilability is greater than 50%.Wherein, the compound that the embodiment of the present invention 13 is prepared In the intracorporal AUC of dog after gastric infusionlastGreater than 15000h*ng/mL.
Test result shows that the compounds of this invention has preferable pharmacokinetic property in dog body.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " embodiment ", " show The description of example ", specific examples or " some examples " etc. means to combine the specific spy of the embodiment, embodiment or example description Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification In, schematic expression of the above terms are necessarily directed to identical embodiment, embodiment or example.Moreover, description Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable Mode combines.In addition, without conflicting with each other, those skilled in the art can be by difference described in this specification Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (8)

1. a kind of compound, the structure with one of:
Or it can pharmaceutically connect The salt received.
2. a kind of pharmaceutical composition, it includes compounds described in claim 1.
3. pharmaceutical composition according to claim 2 further comprises pharmaceutically acceptable carrier, adjuvant, medium Object or their any combination.
4. pharmaceutical composition according to claim 3, further includes additional therapeutic agent, wherein the additional therapeutic agent To treat the drug of azheimer's disease, treating the drug or their combination of nervous disorders.
5. pharmaceutical composition according to claim 4, wherein the additional therapeutic agent is donepezil, nalmefene, Li Pei Ketone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB- 742457, naluzaton, idalopirdine, Tacrine, Rivastigmine, galanthamine, Memantine, mitzapine, Wen Lafa Pungent, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline or it Any combination.
6. pharmaceutical composition described in compound described in claim 1 or claim 2-5 any one is in medicine preparation Purposes, the drug is for preventing, treating or mitigating and 5-HT6Receptor related disease.
7. purposes according to claim 6, wherein described and 5-HT6Receptor related disease is CNS illness, gastrointestinal disease Disease or obesity.
8. purposes according to claim 7, wherein the CNS illness is ADHD, anxiety, disease relating to mental stress Disease, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nervous disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's chorea.
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